Medical School · Year 2 · Immunology · includes a quiz and discussion video

Lecture 8: Hypersensitivity Reactions

Unit 2.7: Immunology

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the classification of hypersensitivity reactions (Types I-IV)
2. Explain the mechanisms and clinical manifestations of Type I hypersensitivity
3. Describe antibody-mediated (Types II and III) hypersensitivity
4. Explain delayed-type hypersensitivity (Type IV)
5. Describe allergic diseases and their management
6. Explain drug hypersensitivity reactions

Lecture Outline

I. Overview of Hypersensitivity

The Gell and Coombs classification system, developed in 1963, remains the foundational framework for understanding hypersensitivity reactions. This schema categorizes immune-mediated tissue damage into four distinct types based on the underlying immunological mechanism and temporal characteristics. Type I reactions are IgE-mediated and occur within minutes of allergen exposure, manifesting as anaphylaxis, allergic rhinitis, or acute asthma. Type II reactions involve IgG or IgM antibodies directed against cell surface or tissue antigens, causing damage over hours to days as seen in autoimmune hemolytic anemia and Goodpasture syndrome. Type III reactions result from immune complex deposition in tissues, leading to complement activation and inflammation over similar timeframes, exemplified by systemic lupus erythematosus and serum sickness. Type IV reactions are T cell-mediated delayed-type hypersensitivity responses, typically manifesting 24-72 hours after antigen exposure, as observed in contact dermatitis and tuberculin skin testing.

The development of hypersensitivity reactions requires distinct sensitization and elicitation phases. During sensitization, the initial encounter with an antigen leads to immune system priming without clinical symptoms. This phase establishes immunological memory through the generation of antigen-specific IgE antibodies (Type I), IgG or IgM antibodies (Types II and III), or memory T cells (Type IV). The elicitation phase occurs upon subsequent antigen encounter, when the pre-existing immune response rapidly mobilizes to cause tissue damage and clinical manifestations. The anamnestic or memory response ensures that subsequent exposures trigger increasingly rapid and potent reactions, explaining why allergic reactions often worsen with repeated exposures and why a negative history of prior exposure does not preclude sensitization from having occurred.

Each type of hypersensitivity reaction involves distinct effector cells and molecules that mediate tissue injury. Type I reactions depend on IgE antibodies bound to high-affinity FcepsilonRI receptors on mast cells and basophils. Type II reactions utilize IgG and IgM antibodies working through complement activation, phagocytosis via Fc receptors, and antibody-dependent cellular cytotoxicity involving NK cells. Type III reactions center on the formation of antigen-antibody immune complexes that activate complement, generating C3a and C5a anaphylatoxins that recruit neutrophils to sites of complex deposition. Type IV reactions employ T cells as the primary effectors, with different subtypes utilizing Th1 cells activating macrophages, Th2 cells recruiting eosinophils, cytotoxic T lymphocytes directly killing target cells, or Th17 cells mobilizing neutrophils.

The clinical significance of hypersensitivity reactions extends across virtually all medical specialties. Allergic diseases affect 20-30% of the population in developed countries, representing a substantial burden of morbidity and healthcare utilization. At the severe end of the spectrum, anaphylaxis constitutes a life-threatening medical emergency requiring immediate intervention. Drug hypersensitivity reactions represent a major cause of morbidity and mortality, complicating treatment decisions and limiting therapeutic options. Furthermore, the mechanisms underlying Types II-IV hypersensitivity contribute fundamentally to autoimmune diseases, where the immune system inappropriately targets self-antigens using these same pathways of tissue destruction.

<image> Panel A: Comprehensive Gell-Coombs classification diagram showing all four hypersensitivity types arranged in quadrants, with each quadrant depicting the key immune cells (mast cells for Type I, antibodies binding cells for Type II, immune complexes for Type III, T cells for Type IV), timing of response (minutes for Type I, hours-days for Types II-III, 24-72 hours for Type IV), and representative diseases. Panel B: Timeline diagram illustrating sensitization versus elicitation phases, showing initial antigen exposure leading to IgE production and mast cell sensitization (no symptoms), followed by re-exposure triggering mast cell degranulation (clinical reaction), with memory cell persistence indicated by a clock symbol. Panel C: Detailed effector cell and molecule comparison across all four types, showing IgE and mast cells for Type I, IgG/IgM with complement and phagocytes for Type II, immune complexes with neutrophils for Type III, and various T cell subsets with macrophages for Type IV, with arrows indicating their mechanisms of tissue damage. Panel D: Clinical prevalence and impact infographic showing that allergic diseases affect 20-30% of population, with pie charts indicating relative contribution of each hypersensitivity type to clinical practice, and icons representing anaphylaxis (emergency), autoimmunity, and drug reactions. </image>

II. Type I Hypersensitivity - Mechanisms

The sensitization phase of Type I hypersensitivity establishes the immunological framework for subsequent allergic reactions. Upon initial allergen exposure, the foreign protein is captured by dendritic cells in barrier tissues such as skin, respiratory mucosa, or gut-associated lymphoid tissue. These antigen-presenting cells process the allergen and migrate to regional lymph nodes, where they present allergen-derived peptides on MHC class II molecules to naive CD4+ T cells. In genetically predisposed individuals, environmental factors and cytokine milieus favor differentiation toward the Th2 phenotype, characterized by production of IL-4, IL-5, and IL-13. The IL-4 produced by these Th2 cells provides the critical signal for B cells to undergo immunoglobulin class switching to IgE. The resulting allergen-specific IgE antibodies enter circulation and bind with high affinity to FcepsilonRI receptors on tissue mast cells and blood basophils, arming these cells for rapid activation upon subsequent allergen encounter.

The effector phase is triggered when re-exposure to the sensitizing allergen occurs, initiating a cascade of cellular events culminating in the allergic reaction. Allergen molecules must be multivalent, possessing multiple epitopes capable of cross-linking two or more IgE antibodies bound to adjacent FcepsilonRI receptors on the mast cell surface. This receptor aggregation triggers intracellular signaling cascades involving protein tyrosine kinases, phospholipase C activation, and calcium influx, leading to two distinct processes: immediate degranulation of preformed granule contents and de novo synthesis of lipid mediators and cytokines. The early phase reaction occurs within minutes, characterized by release of preformed mediators including histamine, which causes vasodilation, increased vascular permeability, and smooth muscle contraction, and tryptase, a serine protease useful as a diagnostic marker of mast cell activation.

Mast cells produce a diverse array of mediators that orchestrate the immediate and sustained features of allergic inflammation. Preformed mediators stored in cytoplasmic granules include histamine, the archetypal mast cell product causing vasodilation, increased permeability, pruritus, and bronchoconstriction, and proteases such as tryptase and chymase that contribute to tissue remodeling and damage. Newly synthesized lipid mediators include leukotrienes C4, D4, and E4, formerly known as slow-reacting substance of anaphylaxis, which cause prolonged bronchoconstriction, mucus secretion, and vascular permeability, and prostaglandin D2, which promotes vasodilation and bronchoconstriction while recruiting Th2 cells. Cytokines synthesized by activated mast cells, including IL-4, IL-5, IL-13, and TNF-alpha, sustain inflammation and recruit additional inflammatory cells, perpetuating the allergic response beyond the immediate reaction.

The late phase response emerges 4-8 hours after allergen exposure and represents a second wave of symptoms mediated by newly recruited inflammatory cells. This phase results from the chemotactic effects of mast cell-derived cytokines and chemokines, which draw eosinophils, basophils, Th2 cells, and additional neutrophils to the site of the allergic reaction. Eosinophils, hallmark cells of allergic inflammation, release major basic protein and eosinophil cationic protein, which damage epithelial tissues and perpetuate inflammation. The late phase is clinically significant because it explains the biphasic nature of some allergic reactions, where patients who initially respond to treatment may experience symptom recurrence hours later. This understanding has important therapeutic implications, particularly for anaphylaxis management, where observation periods are recommended to monitor for late phase reactions.

<image> Panel A: Step-by-step sensitization pathway diagram showing allergen uptake by dendritic cell in epithelium, migration to lymph node, presentation to naive CD4+ T cell, Th2 differentiation with IL-4 production, B cell class switching to IgE, and IgE binding to FcepsilonRI on mast cell surface, with each step labeled and arrows indicating progression. Panel B: Mast cell degranulation illustration showing cross-linking of surface-bound IgE by multivalent allergen, receptor aggregation, intracellular signaling cascade with calcium influx, and exocytosis of preformed granules containing histamine and tryptase, alongside de novo synthesis of lipid mediators and cytokines. Panel C: Comprehensive mast cell mediator diagram organized by category (preformed, lipid, cytokine) showing histamine causing vasodilation and bronchoconstriction, leukotrienes causing prolonged bronchoconstriction, prostaglandin D2, and various cytokines with their target cells and effects. Panel D: Early versus late phase response timeline starting at allergen exposure (time 0), showing immediate mast cell degranulation with clinical symptoms peaking in minutes, followed by resolution, then second wave of symptoms at 4-8 hours with eosinophil and lymphocyte infiltration shown in tissue cross-section. </image>

III. Type I Clinical Manifestations

Anaphylaxis represents the most severe manifestation of Type I hypersensitivity, constituting a medical emergency with potentially fatal consequences. This systemic reaction results from massive, widespread mast cell degranulation triggered by allergen exposure in a sensitized individual. Common triggers include foods (particularly peanuts, tree nuts, shellfish, milk, and eggs), medications (beta-lactam antibiotics, NSAIDs, biological agents), insect stings (Hymenoptera venom from bees, wasps, and hornets), and latex. Clinical manifestations typically begin within minutes of exposure and involve multiple organ systems: cutaneous symptoms include urticaria, flushing, angioedema, and pruritus; respiratory manifestations range from rhinitis and laryngeal edema to bronchospasm and respiratory arrest; cardiovascular collapse with hypotension and shock results from vasodilation and fluid extravasation; and gastrointestinal symptoms include nausea, vomiting, and diarrhea. The first-line treatment for anaphylaxis is intramuscular epinephrine, which counters the pathophysiological effects through alpha-adrenergic vasoconstriction, beta-1 cardiac stimulation, and beta-2 bronchodilation and mast cell stabilization.

Allergic rhinitis affects approximately 20% of the population and significantly impacts quality of life, work productivity, and healthcare costs. This condition results from IgE-mediated reactions to inhaled aeroallergens, including seasonal pollens (trees, grasses, weeds) and perennial allergens (dust mites, animal dander, mold spores, cockroach antigens). Upon allergen contact with sensitized nasal mucosa, mast cell degranulation releases histamine and other mediators, causing the classic symptoms of sneezing, clear rhinorrhea, nasal congestion, and pruritus of the nose, palate, and eyes. Physical examination may reveal pale, boggy nasal turbinates, allergic shiners (dark circles under eyes), the allergic salute (transverse nasal crease from repeated rubbing), and Dennie-Morgan lines (infraorbital folds). Untreated allergic rhinitis can contribute to sinusitis, otitis media, sleep disturbance, and exacerbation of asthma, highlighting the importance of the unified airway concept connecting upper and lower respiratory tract inflammation.

Allergic asthma exemplifies the chronic inflammatory consequences of repeated Type I hypersensitivity reactions in the lower airways. This condition is characterized by reversible airway obstruction, bronchial hyperresponsiveness, and airway inflammation driven by Th2 cells and eosinophils. Allergen exposure in sensitized individuals triggers acute bronchoconstriction through mast cell mediators, followed by a late phase response with eosinophilic inflammation that contributes to mucus hypersecretion, epithelial damage, and airway edema. Chronic, persistent inflammation leads to airway remodeling, including smooth muscle hypertrophy, subepithelial fibrosis, goblet cell hyperplasia, and basement membrane thickening, which may cause fixed airway obstruction over time. Clinical features include episodic wheezing, chest tightness, cough, and dyspnea, often worse at night or with exercise. Management encompasses trigger avoidance, inhaled corticosteroids as the cornerstone of controller therapy, and bronchodilators for symptom relief, with biologics targeting Th2 pathway components (anti-IgE, anti-IL-5, anti-IL-4/13) reserved for severe, refractory cases.

Food allergy represents a growing public health concern, with prevalence increasing substantially over recent decades, particularly in developed countries. IgE-mediated food allergy manifests with rapid onset symptoms, typically within minutes to two hours of ingestion, affecting the skin (urticaria, angioedema), gastrointestinal tract (nausea, vomiting, abdominal pain, diarrhea), respiratory system (rhinorrhea, wheezing), and cardiovascular system (hypotension, anaphylaxis). The eight major food allergens accounting for most reactions include peanut, tree nuts, milk, egg, wheat, soy, fish, and shellfish, with variations in prevalence across different populations and age groups. Diagnosis involves careful history, skin prick testing demonstrating allergen-specific sensitization, measurement of serum allergen-specific IgE, and in some cases, physician-supervised oral food challenges as the gold standard for confirming clinical reactivity. Currently, the mainstay of management is strict allergen avoidance and provision of emergency medications including epinephrine auto-injectors, though emerging therapies such as oral immunotherapy offer hope for inducing desensitization or sustained unresponsiveness in selected patients.

<image> Panel A: Anaphylaxis clinical presentation and emergency management diagram showing patient with labeled symptoms across organ systems (urticaria on skin, laryngeal edema in throat, bronchospasm in lungs, hypotension affecting heart, GI symptoms), alongside treatment algorithm featuring epinephrine auto-injector administration into lateral thigh, IV fluids, airway management, and observation period. Panel B: Allergic rhinitis illustration showing nasal cross-section with pale, edematous turbinates, mast cells releasing histamine, allergen particles (pollen grains, dust mites) entering nasal cavity, and resulting symptoms of sneezing, rhinorrhea, and congestion depicted around a patient face showing allergic shiners and nasal crease. Panel C: Allergic asthma pathophysiology showing normal airway compared to asthmatic airway with bronchoconstriction, mucus plugging, eosinophilic infiltration, epithelial damage, and basement membrane thickening, plus chronic remodeling changes with smooth muscle hypertrophy and subepithelial fibrosis in a longitudinal disease progression panel. Panel D: Food allergy evaluation and management flowchart beginning with clinical history, proceeding through skin prick testing, specific IgE measurement, oral food challenge, leading to management strategies including strict avoidance, epinephrine prescription, and emerging oral immunotherapy protocol with dose escalation phases. </image>

IV. Diagnosis and Treatment of Type I

The diagnosis of Type I hypersensitivity relies on a combination of clinical history, physical examination, and specific immunological testing to identify the causative allergen. Skin prick testing remains the primary in vivo diagnostic method, offering rapid results, high sensitivity, and cost-effectiveness. The procedure involves placing a drop of allergen extract on the forearm or back and introducing it into the epidermis with a lancet, then observing for a wheal-and-flare reaction at 15-20 minutes that indicates allergen-specific IgE on cutaneous mast cells. A positive test requires a wheal diameter at least 3mm larger than the negative saline control, while a histamine positive control confirms skin reactivity. Intradermal testing, where dilute allergen is injected into the dermis, offers greater sensitivity and is particularly useful for venom and drug allergy testing but carries higher risk of systemic reactions. Contraindications to skin testing include antihistamine use (requires discontinuation), dermatographism, widespread skin disease, and history of severe anaphylaxis to the suspected allergen.

In vitro testing for allergen-specific IgE provides an alternative when skin testing is not feasible or desirable. These blood tests, including the ImmunoCAP system, measure circulating IgE antibodies directed against specific allergens without risk of allergic reaction and without interference from antihistamines. Results are reported in standardized units, with higher levels generally correlating with greater likelihood of clinical reactivity, though thresholds vary by allergen and clinical context. Component-resolved diagnostics represent an advancement that measures IgE against individual allergenic proteins within a complex allergen source, helping distinguish true sensitization from cross-reactivity and predict clinical severity. For example, in peanut allergy, sensitization to Ara h 2 correlates with clinical reactivity and anaphylaxis risk, while isolated sensitization to Ara h 8, a PR-10 protein cross-reactive with birch pollen, typically predicts mild oral allergy syndrome. Serum tryptase measurement is valuable in the acute setting, with elevated levels supporting a diagnosis of anaphylaxis when obtained within several hours of the reaction.

Pharmacotherapy for Type I hypersensitivity targets the mediators and cellular pathways driving allergic inflammation. H1-antihistamines remain first-line therapy for allergic rhinitis and urticaria, competitively blocking histamine receptors to relieve pruritus, sneezing, and rhinorrhea, with second-generation agents (cetirizine, loratadine, fexofenadine) preferred for their reduced sedation and anticholinergic effects. Intranasal corticosteroids represent the most effective single therapy for allergic rhinitis, reducing inflammation, congestion, and overall symptom burden with minimal systemic absorption. Leukotriene receptor antagonists such as montelukast block the bronchoconstrictor and pro-inflammatory effects of cysteinyl leukotrienes, providing benefit in allergic rhinitis and as add-on therapy in asthma. For severe allergic disease, omalizumab, a humanized monoclonal anti-IgE antibody, reduces free IgE levels and downregulates FcepsilonRI expression, diminishing mast cell and basophil activation and finding application in moderate-to-severe allergic asthma and chronic spontaneous urticaria.

Allergen immunotherapy represents the only disease-modifying treatment for IgE-mediated allergic disease, inducing tolerance through repeated administration of increasing allergen doses. Subcutaneous immunotherapy (SCIT), the traditional approach, involves a build-up phase of weekly injections with progressively increasing doses, followed by maintenance injections every 2-4 weeks for 3-5 years. The mechanism involves complex immunological changes including generation of allergen-specific regulatory T cells producing IL-10 and TGF-beta, class switching from IgE to IgG4 blocking antibodies, and decreased mast cell and basophil reactivity. Sublingual immunotherapy (SLIT) offers an alternative route with tablets or drops administered daily under the tongue, with FDA-approved products for grass, ragweed, and dust mite allergy providing efficacy with improved convenience and safety profile. Oral immunotherapy (OIT) for food allergy represents an emerging approach, with FDA approval of a peanut OIT product (Palforzia) representing a milestone; however, this treatment achieves desensitization rather than permanent tolerance, requiring continued regular allergen intake to maintain protection, and carries risk of allergic reactions during treatment.

<image> Panel A: Skin prick testing procedure illustration showing forearm with grid of allergen applications, lancet technique introducing allergen into epidermis, magnified view of histamine positive control and negative saline control, and interpretation criteria with measurement of wheal diameter showing positive result greater than 3mm over negative control. Panel B: Component-resolved diagnostics concept for peanut allergy showing peanut with its allergenic components (Ara h 1, 2, 3, 8, 9) mapped to clinical outcomes, demonstrating that Ara h 2 positivity predicts severe systemic reactions while Ara h 8 positivity (birch cross-reactive) predicts mild oral symptoms only. Panel C: Pharmacotherapy mechanism diagram showing antihistamine blocking H1 receptor on blood vessel and nerve (reducing itch and vasodilation), intranasal corticosteroid suppressing inflammatory gene transcription in nasal epithelium, leukotriene antagonist blocking LT receptor in airways, and omalizumab neutralizing free IgE to prevent mast cell sensitization. Panel D: Allergen immunotherapy protocol comparing subcutaneous (SCIT) with weekly build-up injections followed by monthly maintenance, sublingual (SLIT) with daily home administration, and oral (OIT) with daily food allergen dosing, showing the immunological shift from Th2/IgE dominance to Treg/IgG4 tolerance with blocking antibody production. </image>

V. Type II Hypersensitivity

Type II hypersensitivity involves antibodies, predominantly IgG and IgM, directed against antigens on cell surfaces or in extracellular matrix, leading to tissue damage through several distinct mechanisms. Complement activation occurs when antibodies bound to target cells activate the classical pathway, generating the membrane attack complex (MAC) that directly lyses cells, and producing anaphylatoxins C3a and C5a that recruit inflammatory cells. Opsonization results from IgG coating target cells, with Fc regions recognized by FcgammaRI and FcgammaRIII on phagocytes, promoting engulfment and destruction. Antibody-dependent cellular cytotoxicity (ADCC) involves NK cells binding to IgG-coated targets via FcgammaRIII (CD16), triggering release of perforin and granzymes that kill the target cell. A fourth mechanism, unique to certain autoimmune conditions, involves antibodies binding to receptors and either stimulating or blocking their function without necessarily destroying the cell, as seen in Graves disease and myasthenia gravis.

Cytotoxic Type II reactions, where antibodies cause cell destruction, underlie numerous hematologic and organ-specific autoimmune diseases. Autoimmune hemolytic anemia results from antibodies against red blood cell surface antigens, causing complement-mediated intravascular hemolysis or splenic sequestration and extravascular destruction. Immune thrombocytopenic purpura features autoantibodies against platelet glycoproteins, particularly GPIIb/IIIa and GPIb/IX, leading to accelerated platelet clearance by splenic macrophages. Goodpasture syndrome involves autoantibodies against the noncollagenous domain of type IV collagen in glomerular and alveolar basement membranes, causing rapidly progressive glomerulonephritis and pulmonary hemorrhage. In transfusion medicine, Type II mechanisms underlie acute hemolytic transfusion reactions when preformed recipient antibodies (anti-A, anti-B) attack transfused incompatible red cells, and hemolytic disease of the fetus and newborn results from maternal IgG anti-Rh antibodies crossing the placenta to destroy fetal red cells.

Receptor-mediated Type II reactions demonstrate how antibodies can cause disease by interfering with receptor function rather than destroying cells. In Graves disease, autoantibodies against the thyroid-stimulating hormone receptor (TSHR) act as agonists, binding and activating the receptor to cause constitutive thyroid hormone production independent of pituitary control, resulting in hyperthyroidism, diffuse goiter, and distinctive ophthalmopathy. Conversely, in myasthenia gravis, autoantibodies against the nicotinic acetylcholine receptor at the neuromuscular junction act as antagonists, blocking neuromuscular transmission and causing the characteristic fatigable weakness of ocular, bulbar, and limb muscles. Pernicious anemia results from autoantibodies against intrinsic factor or gastric parietal cells, blocking vitamin B12 absorption and causing megaloblastic anemia and neurological complications. These conditions illustrate that Type II hypersensitivity can cause disease through mechanisms beyond simple cell destruction.

Drug-induced Type II hypersensitivity reactions occur when medications become associated with cell surfaces, creating neo-antigens recognized by the immune system. Several mechanisms are recognized: the hapten model, exemplified by penicillin, involves the drug covalently binding to cell surface proteins, with antibodies recognizing the drug-protein complex leading to destruction of drug-coated cells. Drug-induced autoantibody formation occurs with drugs like methyldopa, which triggers production of antibodies that cross-react with native red cell antigens, causing warm autoimmune hemolytic anemia that may persist after drug discontinuation. The innocent bystander mechanism involves drug-antibody immune complexes adsorbing onto cell surfaces, activating complement and causing cytopenia; quinidine-induced thrombocytopenia exemplifies this pattern. Recognition of drug-induced cytopenias is clinically important, as the treatment is drug discontinuation and supportive care, with recovery expected once the offending agent is eliminated.

<image> Panel A: Four mechanisms of Type II hypersensitivity showing: (1) complement activation with antibody-bound cell, C1 binding, cascade activation, and MAC formation causing cell lysis; (2) opsonization with IgG-coated cell being engulfed by macrophage via Fc receptor; (3) ADCC with NK cell binding to IgG-coated target via CD16 and releasing perforin/granzymes; (4) receptor modification showing agonist antibody stimulating receptor versus antagonist antibody blocking receptor. Panel B: Cytotoxic disease examples showing autoimmune hemolytic anemia with antibody-coated RBC being destroyed by splenic macrophage, Goodpasture syndrome with antibodies binding glomerular basement membrane and complement-mediated damage, and hemolytic disease of newborn with maternal anti-Rh IgG crossing placenta to attack fetal RBCs. Panel C: Receptor-mediated disease comparison showing Graves disease with thyroid-stimulating antibodies activating TSHR leading to hormone overproduction and thyroid enlargement, versus myasthenia gravis with antibodies blocking acetylcholine receptors at neuromuscular junction causing muscle weakness, with clinical features of each disease illustrated. Panel D: Drug-induced Type II mechanisms showing penicillin hapten covalently bound to RBC surface creating neo-antigen, methyldopa inducing true autoantibody production against native RBC antigens, and quinidine-antibody immune complexes adsorbing onto platelet surface activating complement, with timeline showing recovery after drug cessation. </image>

VI. Type III Hypersensitivity

Type III hypersensitivity is mediated by immune complexes, aggregates of antigen and antibody that form in circulation or at local tissue sites and deposit in blood vessel walls, glomeruli, joints, and other tissues. When antigens enter the bloodstream and encounter circulating IgG or IgM antibodies, immune complexes of varying sizes form depending on the relative concentrations of antigen and antibody. These complexes can activate the classical complement pathway, generating C3a and C5a anaphylatoxins that serve as potent chemotactic factors for neutrophils. Recruited neutrophils attempt to phagocytose the deposited complexes but, unable to internalize tissue-fixed complexes, undergo frustrated phagocytosis, releasing lysosomal enzymes, reactive oxygen species, and additional inflammatory mediators that damage the surrounding tissue. The resulting inflammation causes vasculitis, glomerulonephritis, or arthritis depending on the site of complex deposition.

The pathogenicity of immune complexes depends on multiple factors that influence their formation, circulation, and deposition. The antigen-to-antibody ratio is critical: at moderate antigen excess, larger lattice-like complexes form that are most pathogenic, while extreme antigen excess yields small complexes that remain soluble, and antibody excess produces complexes that are rapidly cleared. Complex size influences clearance and deposition, with intermediate-sized complexes escaping hepatic and splenic clearance yet being large enough to deposit in vessel walls. The charge of immune complexes affects their interaction with negatively charged basement membranes, with cationic complexes preferentially depositing in glomeruli. Hemodynamic factors also play a role, as complexes tend to deposit at sites of turbulent blood flow such as vascular bifurcations and in filtration organs like the kidney. Deficiencies in early classical complement components (C1q, C2, C4) impair immune complex solubilization and clearance, predisposing to Type III disease.

Clinical manifestations of Type III hypersensitivity include both systemic and localized forms. Serum sickness, the prototype systemic immune complex disease, classically occurred following administration of heterologous antiserum (horse serum antitoxins) and now occurs with certain drugs, particularly beta-lactam antibiotics and chimeric monoclonal antibodies. After a 7-14 day latent period (the time required to mount an antibody response), patients develop fever, urticaria, arthralgias, lymphadenopathy, and sometimes glomerulonephritis; laboratory findings include low complement levels and elevated inflammatory markers. Systemic lupus erythematosus represents a chronic immune complex disease where autoantibodies against nuclear antigens form complexes that deposit in kidneys, skin, joints, and serosal surfaces. Post-streptococcal glomerulonephritis follows streptococcal infection, with streptococcal antigens and host antibodies forming complexes that deposit in glomeruli, causing acute nephritis characterized by hematuria, proteinuria, edema, and hypertension.

The Arthus reaction represents the localized form of Type III hypersensitivity, occurring when antigen is introduced into tissue of an individual with preexisting circulating antibodies. Named after Maurice Arthus who described it in 1903, this reaction manifests as local vasculitis with edema, hemorrhage, and necrosis at the injection site, typically developing over 4-8 hours. The mechanism involves formation of immune complexes at the injection site, local complement activation, neutrophil infiltration, and vascular damage. Clinically relevant examples include hypersensitivity pneumonitis (also called extrinsic allergic alveolitis), where repeated inhalation of organic antigens by sensitized individuals causes localized immune complex reactions in the lungs. Farmer's lung results from thermophilic actinomycete antigens in moldy hay, bird fancier's lung from avian proteins in bird droppings and feathers, and humidifier lung from contaminated water reservoirs. These conditions present with fever, dyspnea, and cough hours after exposure, with chronic exposure leading to pulmonary fibrosis.

<image> Panel A: Immune complex formation and deposition diagram showing antigen and antibody combining at optimal ratio to form large lattice complexes, circulation through bloodstream, and deposition at vascular bifurcation with complement activation generating C3a and C5a chemotactic signals attracting neutrophils to the site. Panel B: Factors affecting immune complex pathogenicity including antigen:antibody ratio curve showing moderate antigen excess forming pathogenic complexes, size spectrum from small (cleared) to intermediate (deposited) to large (cleared), charge interaction with negatively charged basement membrane, and role of complement deficiency in impaired clearance. Panel C: Serum sickness clinical presentation and timeline showing exposure at day 0, antibody production during latent period, immune complex formation around day 7-10, and clinical manifestations (fever, rash, arthralgia, lymphadenopathy) peaking at day 10-14 with laboratory findings of low C3/C4 and elevated ESR, followed by resolution as antigen eliminated. Panel D: Localized Type III reaction illustration showing Arthus reaction at skin injection site with immune complex formation, complement activation, neutrophil infiltration and vascular damage, alongside comparison with hypersensitivity pneumonitis showing inhaled antigen exposure, alveolar immune complex formation, and resulting inflammation in the lung parenchyma. </image>

VII. Type IV Hypersensitivity

Type IV hypersensitivity, also known as delayed-type hypersensitivity (DTH), is fundamentally distinct from the antibody-mediated Types I-III in that T lymphocytes serve as the primary effector cells. This category encompasses several subtypes based on the T cell population involved and the predominant effector mechanism. Type IVa reactions involve Th1 cells that secrete IFN-gamma, activating macrophages to become potent effector cells capable of killing intracellular pathogens and forming granulomas; the tuberculin skin test and granulomatous inflammation exemplify this subtype. Type IVb reactions are driven by Th2 cells producing IL-4 and IL-5, recruiting eosinophils as effector cells; this mechanism contributes to chronic allergic inflammation. Type IVc reactions involve cytotoxic T lymphocytes (CTLs) that directly kill target cells expressing the sensitizing antigen; contact dermatitis and some drug reactions involve this mechanism. Type IVd reactions feature Th17 cells producing IL-17 that recruits neutrophils, as seen in acute generalized exanthematous pustulosis (AGEP).

The classic delayed-type hypersensitivity reaction proceeds through sensitization and elicitation phases, with distinctive kinetics reflecting the time required for T cell activation and effector cell recruitment. During sensitization, antigen is taken up by dendritic cells, processed, and presented on MHC class II molecules to naive CD4+ T cells in draining lymph nodes, generating antigen-specific memory T cells. Upon re-exposure, antigen is again presented by local antigen-presenting cells to memory T cells, which rapidly activate and release cytokines, particularly IFN-gamma. This cytokine activates tissue macrophages, increasing their phagocytic capacity, antimicrobial activity, and ability to present antigen, while also recruiting additional mononuclear cells to the site. The reaction peaks at 48-72 hours, accounting for the "delayed" descriptor, and manifests as induration (tissue swelling and firmness) at the site due to cellular infiltration and edema. The tuberculin (Mantoux) skin test utilizes this principle, with injection of purified protein derivative (PPD) from Mycobacterium tuberculosis eliciting a DTH response in individuals previously infected with or vaccinated against tuberculosis.

Granulomatous inflammation represents a specialized form of Type IV hypersensitivity that develops in response to persistent antigens that cannot be eliminated. When macrophages encounter resistant intracellular pathogens or indigestible foreign materials, chronic Th1 activation leads to macrophage transformation into epithelioid cells, which resemble epithelial cells with abundant cytoplasm and enhanced secretory function. These epithelioid macrophages aggregate into organized structures called granulomas, often with multinucleated giant cells formed by macrophage fusion at the center, surrounded by a collar of lymphocytes. The granuloma serves to wall off and contain pathogens that cannot be eliminated, but the persistent inflammation causes tissue damage and fibrosis. Classic examples include caseating granulomas of tuberculosis with central necrosis, the non-caseating granulomas of sarcoidosis, and the granulomatous inflammation in Crohn's disease and foreign body reactions.

The clinical spectrum of Type IV hypersensitivity extends across infectious, autoimmune, and environmental contexts. In infectious diseases, Type IV responses are essential for controlling intracellular pathogens including mycobacteria, fungi (histoplasmosis, coccidioidomycosis), and certain parasites (leishmania), though excessive responses contribute to tissue damage. Autoimmune diseases with Type IV mechanisms include type 1 diabetes mellitus, where CD8+ T cells destroy pancreatic beta cells; Hashimoto thyroiditis, with T cell-mediated thyroid destruction; and multiple sclerosis, where T cells reactive to myelin antigens drive demyelination. In drug hypersensitivity, Type IV reactions cause delayed morbilliform eruptions, as well as severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome and toxic epidermal necrolysis. The diversity of Type IV clinical manifestations reflects the multiple T cell subtypes and effector mechanisms encompassed within this category.

<image> Panel A: Type IV subtypes diagram showing four parallel pathways: IVa with Th1 cell, IFN-gamma secretion, and activated macrophage killing intracellular bacteria; IVb with Th2 cell, IL-4/IL-5 secretion, and eosinophil recruitment; IVc with CD8+ CTL directly killing target cell via perforin/granzyme; IVd with Th17 cell, IL-17 secretion, and neutrophil recruitment forming pustules. Panel B: Delayed-type hypersensitivity timeline showing sensitization phase (first exposure, T cell priming), then re-exposure triggering memory T cell activation, IFN-gamma release peaking at 24-48 hours, macrophage activation, and clinical induration peak at 48-72 hours, with Mantoux test reading illustration showing measurement of induration. Panel C: Granuloma formation progressive diagram showing initial macrophage engulfing persistent pathogen, chronic Th1 stimulation with IFN-gamma, macrophage transformation to epithelioid cells, organization into mature granuloma with giant cells centrally and lymphocyte collar peripherally, and comparison of caseating (tuberculosis) versus non-caseating (sarcoidosis) granuloma histology. Panel D: Clinical spectrum of Type IV reactions showing tuberculin skin test on arm, granulomatous lung disease chest imaging, autoimmune thyroiditis with T cell infiltration of thyroid, and drug-induced delayed skin eruption with morbilliform rash pattern, representing the range of Type IV manifestations. </image>

VIII. Contact Dermatitis

Allergic contact dermatitis represents a Type IV hypersensitivity reaction occurring in the skin following exposure to low molecular weight chemicals that act as haptens. These small molecules are inherently non-immunogenic but become antigenic when they penetrate the epidermis and bind covalently to skin proteins, creating hapten-protein conjugates recognized as foreign. During sensitization, Langerhans cells (epidermal dendritic cells) take up and process these neo-antigens, migrate to regional lymph nodes, and present them to naive T cells, generating hapten-specific effector and memory T cells. Upon subsequent exposure, the elicitation phase occurs when hapten again penetrates skin and is presented locally to memory T cells, which release IFN-gamma and other cytokines, recruiting inflammatory cells and causing the characteristic eczematous dermatitis. Both CD4+ Th1 cells and CD8+ cytotoxic T cells contribute to the inflammatory response, with CTLs directly killing keratinocytes displaying hapten-modified proteins.

The list of common contact allergens is extensive, reflecting the diverse chemical exposures of daily life. Urushiol, the oleoresin from plants of the Toxicodendron genus (poison ivy, poison oak, and poison sumac), is the most common cause of allergic contact dermatitis in North America, with sensitization rates exceeding 50% in the population. Nickel, present in jewelry, belt buckles, zippers, and cell phones, is the leading cause of contact allergy worldwide, disproportionately affecting women due to ear piercing. Fragrance ingredients in perfumes, cosmetics, and personal care products represent another major allergen category. Rubber accelerators and antioxidants cause allergy to latex gloves and elastic in clothing. Preservatives including methylisothiazolinone and formaldehyde releasers in cosmetics and household products have emerged as increasingly common sensitizers. Topical medications, particularly neomycin and bacitracin antibiotics, can cause contact dermatitis, ironically worsening the skin conditions they are intended to treat.

Patch testing is the diagnostic gold standard for identifying the causative allergen in suspected allergic contact dermatitis. The procedure involves applying standardized concentrations of potential allergens in small chambers (Finn chambers) to the patient's upper back, where they remain under occlusion for 48 hours. Readings are taken at 48 hours when chambers are removed, and again at 72-96 hours to capture delayed reactions and confirm true allergic responses versus irritant reactions. Positive reactions are graded from 1+ (erythema and slight infiltration) to 3+ (vesicles, bullae, and spreading reaction), while irritant reactions typically show sharply demarcated erythema without infiltration. Standard series panels test for the most common allergens, with additional specialized panels for occupation-specific exposures (hairdressers, healthcare workers, metalworkers). Identifying the relevant allergen is crucial, as the only definitive treatment is allergen avoidance, which requires detailed patient education about sources of exposure.

Distinguishing allergic contact dermatitis from irritant contact dermatitis is clinically important, as the conditions have different etiologies, courses, and management strategies. Irritant contact dermatitis results from direct cytotoxic damage to the skin by chemical or physical agents, without immune involvement; it can occur on first exposure and affects anyone with sufficient exposure intensity. Common irritants include soaps, detergents, solvents, acids, alkalis, and repeated wet-dry cycles (wet work). Clinically, irritant dermatitis typically remains confined to the area of contact with well-demarcated borders, while allergic contact dermatitis often spreads beyond the contact area and may show a more diffuse or patchy distribution. Irritant reactions tend to cause burning or stinging rather than the pruritus characteristic of allergic reactions. However, the conditions may coexist, with damaged irritated skin being more susceptible to allergen penetration and sensitization. Treatment of irritant contact dermatitis focuses on eliminating exposure to the irritant and restoring the skin barrier, while allergic contact dermatitis additionally requires identification and avoidance of the specific allergen through patch testing.

<image> Panel A: Allergic contact dermatitis pathogenesis showing hapten molecule penetrating stratum corneum, binding to carrier protein to form hapten-protein complex, uptake by Langerhans cell, migration to lymph node and T cell sensitization, then elicitation phase with local hapten presentation to memory T cells, cytokine release, and resulting eczematous inflammation with spongiosis and lymphocyte infiltration. Panel B: Common contact allergens visual guide showing urushiol from poison ivy leaf, nickel in earring, fragrance molecules in perfume bottle, rubber chemicals in medical gloves, and neomycin in antibiotic ointment tube, with prevalence statistics and typical exposure scenarios for each. Panel C: Patch testing procedure illustration showing application of Finn chambers with allergens to patient's back, 48-hour occlusion period, removal and reading at 48 hours with marking of test sites, second reading at 72-96 hours, and grading scale from negative (no reaction) to 3+ (vesicles and spreading), with examples of positive and irritant reactions compared. Panel D: Comparison table visualization of allergic versus irritant contact dermatitis showing differences in mechanism (immune versus direct toxicity), sensitization requirement (yes versus no), onset timing (24-96 hours versus immediate to hours), distribution (spreads beyond versus limited to contact), morphology (papulovesicular with indistinct borders versus well-demarcated erythema), and symptoms (pruritus versus burning). </image>

IX. Drug Hypersensitivity

Drug hypersensitivity reactions represent adverse effects mediated by immunological mechanisms, encompassing all four Gell and Coombs types and presenting significant diagnostic and management challenges. Type I (IgE-mediated) reactions cause immediate symptoms within minutes to hours, manifesting as urticaria, angioedema, bronchospasm, and anaphylaxis; penicillin allergy is the prototype. Type II (cytotoxic) reactions cause drug-induced cytopenias as discussed previously. Type III (immune complex) reactions cause serum sickness-like disease. Type IV (T cell-mediated) reactions are responsible for delayed eruptions occurring days to weeks after drug initiation, ranging from mild morbilliform rashes to life-threatening severe cutaneous adverse reactions (SCARs). The distinction between immediate and delayed reactions has critical implications for diagnostic testing and management, as skin prick testing and drug-specific IgE detect Type I sensitization, while patch testing and lymphocyte activation tests are relevant for Type IV reactions.

Severe cutaneous adverse reactions (SCARs) represent the most dangerous spectrum of drug hypersensitivity, with significant morbidity and mortality. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) form a spectrum of mucocutaneous reactions characterized by epidermal necrosis and detachment, distinguished by body surface area involved: SJS affects less than 10% BSA, SJS/TEN overlap affects 10-30%, and TEN affects more than 30%. These conditions typically begin 1-3 weeks after drug initiation with prodromal fever and malaise, followed by development of painful erythematous and purpuric macules that coalesce and develop central necrosis, with mucous membrane erosions affecting oral, ocular, and genital surfaces. TEN resembles extensive burns and requires similar intensive care management. Drug reaction with eosinophilia and systemic symptoms (DRESS) presents 2-8 weeks after drug initiation with rash, fever, facial edema, lymphadenopathy, eosinophilia, and internal organ involvement (hepatitis, nephritis, pneumonitis); mortality reaches 10% even with treatment. Acute generalized exanthematous pustulosis (AGEP) causes rapid onset of sterile pustules on erythematous skin, typically resolving quickly after drug discontinuation.

Certain drug classes are disproportionately associated with hypersensitivity reactions, and understanding these associations guides clinical management. Beta-lactam antibiotics cause both immediate IgE-mediated reactions and delayed T cell-mediated reactions, with penicillin being the most common cause of drug-induced anaphylaxis. Sulfonamides, particularly sulfamethoxazole, are strongly associated with SJS/TEN and DRESS, especially in HIV-infected patients. Allopurinol is a leading cause of SJS/TEN, with strong HLA associations (HLA-B58:01 in Asian populations) enabling genetic screening to prevent reactions. Anticonvulsants, particularly aromatic compounds (carbamazepine, phenytoin, lamotrigine), cause DRESS and SJS/TEN, with HLA-B15:02 associated with carbamazepine-induced SJS/TEN in Asian populations. Non-steroidal anti-inflammatory drugs (NSAIDs) cause both immunological (IgE-mediated, T cell-mediated) and non-immunological (COX-1 inhibition-related) hypersensitivity reactions, requiring careful characterization to determine safe alternatives.

Drug allergy evaluation employs multiple testing modalities depending on the reaction type and drug involved. Skin testing is most useful for immediate IgE-mediated reactions, with validated reagents available for penicillin (major and minor determinants) that can reliably exclude IgE-mediated penicillin allergy when negative. Skin testing for other drugs is less standardized and has lower negative predictive value. Drug-specific IgE assays are available for some drugs (penicillins, chlorhexidine) but not others. Patch testing can identify causative drugs in delayed reactions, particularly fixed drug eruption and DRESS, though sensitivity varies by drug. The drug provocation test (challenge) remains the gold standard for confirming or excluding drug allergy but carries risk and is contraindicated after severe reactions. Pharmacogenomic testing for HLA alleles associated with drug hypersensitivity (HLA-B57:01 for abacavir, HLA-B15:02 and HLA-B*58:01 for various drugs in specific populations) enables prevention of severe reactions in at-risk individuals.

<image> Panel A: Drug hypersensitivity classification grid showing Type I (immediate: urticaria, angioedema, anaphylaxis), Type II (cytotoxic: hemolytic anemia, thrombocytopenia), Type III (immune complex: serum sickness), and Type IV (delayed: morbilliform rash, SJS/TEN, DRESS, AGEP) with example drugs for each category and timing of onset indicated on timeline. Panel B: SCAR spectrum illustration showing SJS with less than 10% BSA detachment and mucosal involvement, SJS/TEN overlap at 10-30% BSA, and TEN with greater than 30% BSA showing full-thickness epidermal necrosis resembling burn injury, plus DRESS presentation with facial edema, rash, and organ involvement icons, and AGEP with sterile pustules on erythematous base. Panel C: High-risk drug visualization showing molecular structures and clinical associations for penicillin (anaphylaxis), allopurinol (SJS/TEN with HLA-B58:01), carbamazepine (DRESS and SJS/TEN with HLA-B15:02), sulfonamides (SJS/TEN, especially in HIV), and NSAIDs (both immunological and COX-1 mediated reactions with pathway diagram). Panel D: Drug allergy evaluation algorithm showing immediate reaction pathway (skin prick test, intradermal test, specific IgE, drug challenge if negative) versus delayed reaction pathway (patch testing, lymphocyte tests, clinical history) with pharmacogenomic screening sidebar for HLA typing before high-risk drugs in appropriate populations. </image>

X. Special Considerations

Penicillin allergy represents one of the most commonly reported drug allergies, yet studies consistently demonstrate that the vast majority of patients labeled penicillin-allergic can safely receive these antibiotics. Approximately 10% of hospitalized patients report penicillin allergy, but when formally evaluated, less than 1% have true IgE-mediated allergy. This discrepancy results from several factors: many reported reactions were never truly allergic (gastrointestinal upset, coincident viral exanthems); IgE-mediated penicillin allergy wanes over time, with 50% of patients losing sensitivity within 5 years and 80% within 10 years; and non-specific symptoms are often attributed to allergy without testing. The consequences of an unverified penicillin allergy label are significant: patients receive broader-spectrum, less effective, or more expensive antibiotics, contributing to antimicrobial resistance, increased Clostridioides difficile infections, longer hospital stays, and higher healthcare costs. Penicillin allergy de-labeling through formal skin testing and challenge has emerged as an important quality and safety initiative, allowing safe use of optimal antibiotics in patients who were never truly allergic or who have lost sensitivity.

NSAID hypersensitivity presents a complex clinical challenge because these widely used medications cause adverse reactions through multiple distinct mechanisms. Cross-reactive (or cross-intolerant) NSAID hypersensitivity is the most common pattern, resulting not from immunological sensitization but from the pharmacological effect of COX-1 inhibition, which shunts arachidonic acid metabolism toward leukotriene production. This manifests as NSAID-exacerbated respiratory disease (AERD, formerly Samter's triad) with asthma, nasal polyposis, and reactions to COX-1 inhibitors, or as NSAID-exacerbated cutaneous disease with chronic urticaria worsened by NSAIDs. Patients with cross-reactive hypersensitivity react to structurally unrelated NSAIDs that share COX-1 inhibitory activity but tolerate selective COX-2 inhibitors and weak COX-1 inhibitors like acetaminophen. In contrast, selective (or single-drug) NSAID hypersensitivity involves IgE-mediated or T cell-mediated reactions to a specific NSAID structure, with patients tolerating chemically unrelated NSAIDs. Distinguishing these patterns is essential for recommending appropriate alternatives.

Latex allergy emerged as a significant occupational and medical concern in the 1980s-1990s, particularly affecting healthcare workers with frequent glove exposure and patients with spina bifida or those requiring multiple surgeries. Type I IgE-mediated latex allergy causes contact urticaria, rhinoconjunctivitis, asthma, and potentially anaphylaxis upon contact with natural rubber latex proteins, with reactions occurring within minutes of exposure. Cross-reactivity between latex proteins and structurally similar proteins in certain fruits creates the latex-fruit syndrome, where latex-allergic individuals may react to banana, avocado, kiwi, chestnut, and other foods. Type IV delayed contact dermatitis to rubber accelerators and antioxidants (not latex proteins themselves) is more common than Type I allergy. The transition to nitrile and other synthetic gloves in healthcare settings has reduced new latex sensitization, though established latex allergy persists and requires continued vigilance with latex-free environments for surgical procedures and medical care.

Eosinophilia serves as a common thread connecting many hypersensitivity reactions and provides diagnostic utility. Eosinophils are hallmark cells of allergic inflammation, recruited and activated by IL-5 from Th2 cells and mast cells. Peripheral blood eosinophilia (>500 cells/microL) raises suspicion for allergic diseases (asthma, allergic rhinitis, atopic dermatitis), parasitic infections, drug reactions (particularly DRESS), eosinophilic gastrointestinal diseases, and hypereosinophilic syndromes. In eosinophilic esophagitis, eosinophils infiltrate the esophageal mucosa causing dysphagia and food impaction, often in association with other atopic conditions. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) presents with asthma, eosinophilia, and vasculitis. The therapeutic relevance of eosinophils is demonstrated by the success of anti-IL-5 biologics (mepolizumab, benralizumab) in eosinophilic asthma and other eosinophil-driven conditions, representing targeted intervention in the pathway of allergic inflammation.

<image> Panel A: Penicillin allergy de-labeling diagram showing 10% of patients with reported penicillin allergy at top, funnel narrowing to less than 1% with true IgE-mediated allergy after testing, with reasons for false labeling (viral exanthem, GI upset, waning sensitivity with time graph showing 50% loss at 5 years, 80% at 10 years), and consequences of unverified label (inferior antibiotics, increased CDI, resistance, cost) alongside de-labeling pathway with skin test and challenge. Panel B: NSAID hypersensitivity classification showing cross-reactive pattern (COX-1 inhibition, leukotriene shunting, reaction to all NSAIDs, tolerance of COX-2 inhibitors) with clinical phenotypes (AERD with asthma and polyps, NSAID-exacerbated urticaria) versus selective/single-drug pattern (IgE or T cell mediated to specific drug structure, tolerance of other NSAIDs) with management algorithm for each type. Panel C: Latex allergy illustration showing natural rubber latex protein as allergen, IgE-mediated Type I reaction with contact urticaria, rhinitis, anaphylaxis symptoms on healthcare worker using latex gloves, latex-fruit cross-reactivity diagram showing molecular mimicry between latex proteins and banana, avocado, kiwi, and chestnut, plus Type IV reaction to rubber accelerators causing contact dermatitis. Panel D: Eosinophilia clinical significance showing eosinophil cell with IL-5 receptor, IL-5 produced by Th2 cell driving eosinophil proliferation and survival, differential diagnosis list (allergic disease, parasites, DRESS, eosinophilic GI disease, hypereosinophilic syndrome, EGPA), and anti-IL-5 targeted therapy mechanism with mepolizumab and benralizumab blocking eosinophil production and survival. </image>

Summary

• Type I hypersensitivity is IgE-mediated with immediate onset (minutes) involving mast cell degranulation, causing anaphylaxis, allergic rhinitis, asthma, and food allergy
• Type II hypersensitivity involves IgG or IgM antibodies against cell surface or tissue antigens, causing autoimmune hemolytic anemia, Goodpasture syndrome, Graves disease, and myasthenia gravis
• Type III hypersensitivity results from immune complex deposition causing complement activation and neutrophil-mediated tissue damage, as seen in serum sickness, lupus nephritis, and post-streptococcal glomerulonephritis
• Type IV hypersensitivity is T cell-mediated with delayed onset (24-72 hours), including contact dermatitis, tuberculin skin testing, granulomatous inflammation, and drug reactions
• Anaphylaxis is a severe systemic Type I reaction requiring immediate treatment with intramuscular epinephrine as first-line therapy
• Allergic diseases (rhinitis, asthma, food allergy) are managed with allergen avoidance, antihistamines, corticosteroids, and immunotherapy for disease modification
• Severe cutaneous adverse reactions (SCARs) including SJS/TEN and DRESS are T cell-mediated drug hypersensitivity reactions with significant morbidity and mortality
• Contact dermatitis diagnosis relies on patch testing to identify causative haptens, with treatment centered on allergen avoidance
• Penicillin allergy de-labeling is an important initiative, as most patients with reported allergy can safely receive penicillins after formal evaluation
• Eosinophilia is a hallmark of allergic inflammation and guides both diagnosis and treatment with anti-IL-5 biologics in severe eosinophilic diseases

Key Terms

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