Classification of Hypersensitivity Reactions

Slide 1 · Classification of Hypersensitivity Reactions

Mechanism → tissue injury → clinical phenotype

Diseases of the immune system

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives: Mechanism before memorization

1

Identify the immune effector that defines each hypersensitivity type.

2

Explain how each effector produces its characteristic tissue lesion.

3

Use clinical and morphologic evidence to classify representative diseases.

4

Recognize overlap and avoid treating classification as mutually exclusive.

Slide 3 · Hypersensitivity is injurious immunity

An immune response becomes a cause of tissue injury

The same immune effectors that defend against pathogens can become excessive, inadequately regulated, or misdirected against harmless or self antigens.

Slide 4 · Two broad sources of initiating antigen

Exogenous antigens

Environmental or microbial material: Pollen, foods, dust, drugs, microbial proteins and chemicals.

The initiating target may be otherwise harmless.

Endogenous self antigens

Autologous molecules targeted in autoimmune disease.

Recognition of self can provoke antibody-mediated or T-cell-mediated injury.

Slide 5 · Why protective immunity becomes harmful

Normal effector mechanisms

Excessive / misdirected activation

Insufficient regulation

Tissue damage

Pathogenicity depends on the target, magnitude, location and persistence of the response.

Slide 6 · Sensitization changes subsequent responses

1

Initial antigen exposure may activate lymphocytes and generate specific effector or memory populations.

2

Repeat exposure can trigger a faster or stronger response in a sensitized individual.

3

The final manifestation depends on the effector pathway—not on the mere presence of prior exposure.

“Hypersensitivity” historically refers to acquired sensitivity after exposure.

Slide 7 · Immune defense and immunopathology share effectors

Adaptive recognition

B-cell antibodies and antigen-specific T cells provide recognition and adaptive immune responses.

Innate tissue effectors

Mast cells, complement, phagocytes and inflammatory leukocytes amplify or execute tissue injury.

Slide 8 · The classification is mechanistic—not merely temporal

Four major reaction types (I–IV)

Each category links an initiating immune mechanism with downstream effectors, histopathologic lesions and prototype clinical disorders.

Slide 9 · The four mechanistic classes at a glance

TYPE I

IgE + mast cells

Immediate / allergic

TYPE II

IgG (± IgM) at tissue target

Antibody-mediated

TYPE III

Antigen–antibody complexes

Immune complex–mediated

TYPE IV

CD4+ / CD8+ T lymphocytes

T-cell-mediated

Slide 10 · Antibodies and T cells define different branches

Antibody-associated injury

Type I: IgE / mast cells.

Type II: Antibody directed at fixed cell or tissue antigens.

Type III: Deposited antigen–antibody complexes.

T-cell-associated injury

Type IV: Sensitized CD4+ or CD8+ T lymphocytes.

Cytokine-driven inflammation and/or direct cytotoxicity.

Slide 11 · Location of the antigen clarifies the mechanism

Fixed target (Type II)

Cell surface receptor, blood-cell membrane or tissue basement membrane.

Antibody binds a pre-existing cellular / tissue location.

Deposited complexes (Type III)

Antigen and antibody form complexes in blood or locally; Deposits develop in tissues.

Complex-triggered inflammation is central.

Slide 12 · Characteristic lesions are mechanistic fingerprints

Type

Typical tissue response

Predominant mechanism

I

Edema, mucus, smooth muscle contraction

Mast-cell mediators; Often eosinophilic inflammation

II

Cell loss, inflammation or dysfunction

IgG / complement / Fc effector pathways

III

Inflammation, vasculitis and fibrinoid necrosis

Deposited immune complexes recruit leukocytes

IV

Mononuclear inflammation, granulomas or cell killing

Cytokine-driven and cytotoxic T-cell responses

Slide 13 · Timing is a clue, not the definition

Classify by effector mechanism

“Immediate” is typical of sensitized IgE–mast-cell reactions and “delayed” is characteristic of some T-cell responses. Chronic diseases may combine multiple mechanisms.

Slide 14 · Type I: IgE and mast cells initiate injury

Th2-skewed response

IgE production

IgE-bound mast cells

Mediator release

The resulting vascular, smooth-muscle and inflammatory effects produce allergic disease.

Slide 15 · Type I begins with immune sensitization

Allergen exposure

Th2 / Tfh help

B-cell IgE production

IgE on mast cells

Subsequent allergen challenge activates surface-bound IgE–mast-cell systems.

Slide 16 · Allergen challenge activates sensitized mast cells

Allergen binds surface IgE

Mast-cell activation

Release of vasoactive mediators

Tissue reaction

The rapid reaction reflects pre-armed mast cells, not newly synthesized antibodies.

Slide 17 · Type I has rapid and inflammatory components

Preformed / rapid mediators

Mast-cell products produce vasodilation, vascular leakage, smooth-muscle reactions and glandular secretion.

These appear within minutes.

Cytokine-mediated amplification

Mast cells and type 2 immune cells recruit eosinophils and additional leukocytes.

The late phase may persist for days.

Slide 18 · IgE–mast-cell activation alters tissue function

Mast-cell activation

Vascular dilation / leak

Edema + tissue swelling

Symptoms or obstruction

Vascular changes account for wheals, mucosal swelling and portions of anaphylaxis.

Slide 19 · Type I also acts on smooth muscle and glands

Smooth-muscle contraction

Airway smooth muscle contraction contributes to bronchospasm and airflow obstruction in allergic responses.

Glandular secretion

Increased secretions contribute to rhinorrhea and mucus-rich airway symptoms.

Slide 20 · Early and late phases of Type I reactions

Allergen challenge

Minutes: Vascular / muscle effects

2–24 h: Leukocyte infiltration

Persistence: Mucosal injury / inflammation

The late response can arise without a second antigen exposure.

Slide 21 · Inflammatory cells define the Type I late phase

Eosinophils and other leukocytes enter the affected tissue.

Neutrophils, basophils, monocytes and CD4+ T cells may also be present.

Inflammatory infiltration can damage mucosal epithelial cells.

Repeated episodes explain why many allergic disorders are chronic.

Slide 22 · Type I phenotype follows the portal of exposure

Site

Key local response

Example presentation

Skin

Mast-cell mediator response

Urticaria, wheals or other cutaneous reactions

Nose / eye

Vascular leak and glandular secretion

Rhinitis and conjunctivitis

Airway

Bronchospasm, mucus and inflammation

Atopic bronchial asthma

Systemic

Widespread vascular and airway effects

Anaphylaxis

Slide 23 · Systemic Type I hypersensitivity can be fatal

Systemic allergen exposure

Widespread mast-cell activation

Vascular shock + bronchospasm

Life-threatening anaphylaxis

The same IgE–mast-cell pathway may produce localized allergy or systemic collapse.

Slide 24 · Recognize Type I lesions at two time points

Immediate changes

Vasodilation, edema, glandular secretion and smooth-muscle spasm; Phenotype varies by organ.

Later tissue reaction

Eosinophils and additional recruited leukocytes; Tissue inflammation and possible epithelial injury.

Slide 25 · Type I classification depends on the pathway

IgE + mast cell + mediator injury

Anaphylaxis, allergic rhinitis and atopic asthma are prototypes; The presence of wheezing or edema alone is not enough to assign a hypersensitivity type.

Slide 26 · Type II targets antigens at fixed sites

IgG (occasionally IgM) binds cell or tissue antigens

Cell destruction, complement/Fc receptor–mediated inflammation, or receptor dysfunction can follow direct antibody binding.

Slide 27 · Type II has three major injury pathways

Antibody binds cell / tissue

Opsonization / lysis

Cell depletion

Inflammation

Tissue injury

Functional change

Stimulation / blockade

Different phenotypes; The common starting point is target-bound antibody.

Slide 28 · Fc receptors enable Type II phagocytosis

IgG coats a target cell

Phagocyte recognizes IgG Fc

Engulfment of coated cell

Cell depletion

Antibody-coated erythrocytes and platelets are particularly informative examples.

Slide 29 · Complement amplifies Type II cell clearance

IgG / IgM binds target

Classical complement activation

C3b coats the cell

Complement-receptor phagocytosis

C3b is an opsonin: Complement activation need not always end in direct lysis.

Slide 30 · Two antibody-associated ways to destroy cells

Phagocytosis

Fc- and C3b-receptor recognition promotes uptake and intraphagocytic destruction of coated cells.

Complement-mediated lysis

Terminal complement membrane attack complexes can disrupt target-cell membranes and cause osmotic lysis.

Slide 31 · ADCC is a possible mechanism—not a universal explanation

Antibody-dependent cellular cytotoxicity

IgG-coated targets may be killed by Fc-receptor-bearing cells, including NK cells. Its contribution to common hypersensitivity diseases is uncertain.

Slide 32 · Autoimmune hemolytic anemia exemplifies Type II cell loss

Antibody binds RBC membrane

RBC opsonization

Phagocytic cell removal

Hemolysis + anemia

The primary injured target is the circulating erythrocyte itself.

Slide 33 · Anti-basement-membrane disease exemplifies fixed-tissue injury

Antibody targets basement membrane

Complement / Fc activation

Leukocyte recruitment

Nephritis ± lung hemorrhage

Goodpasture syndrome is the prototype listed Table 6.1.

Slide 34 · Type II inflammation follows antibody deposition

Antibody fixed in tissue

Complement C5a + Fc signaling

Neutrophil / monocyte activation

Proteases + reactive oxygen species

Inflammation damages extracellular matrix and nearby resident cells.

Slide 35 · Receptor blockade: Myasthenia gravis

Anti-receptor antibody

Impaired acetylcholine signaling

Defective neuromuscular transmission

Muscle weakness

A functional antibody effect may predominate even without major visible tissue necrosis.

Slide 36 · Receptor stimulation: Graves disease

Antibody binds TSH receptor

Receptor is stimulated

Thyroid hormone production rises

Hyperthyroidism

Type II reactions can imitate a normal agonist rather than block receptor function.

Slide 37 · Type II cellular loss differs from altered function

Destructive responses

Erythrocyte depletion, platelet loss or inflammation in fixed tissues can result from opsonization and complement/Fc effectors.

Non-destructive responses

Antibodies may block signaling (myasthenia gravis) or stimulate receptors (Graves disease).

Slide 38 · Selected Type II prototypes distinguish submechanisms

Disease

Fixed antigenic target

Dominant expression

Autoimmune hemolytic anemia

RBC membrane

Opsonization; Cell loss

Goodpasture syndrome

Glomerular / alveolar BM

Antibody-driven inflammation

Myasthenia gravis

Acetylcholine receptor

Transmission blockade ± complement injury

Graves disease

TSH receptor

Functional receptor stimulation

Slide 39 · Type III injury requires pathogenic immune complexes

Antigen–IgG complexes deposit in tissues

Immune complexes formed in the circulation or locally recruit inflammatory effectors; The antigen need not be an intrinsic tissue structure.

Slide 40 · Type III: Formation → deposition → inflammation

Antigen + antibody

Immune complex formation

Deposition in tissues

Complement + leukocytes

Release of injurious mediators causes vasculitis and other inflammatory lesions.

Slide 41 · Type III complexes form in two settings

Circulating complexes

Antigen and antibody combine in the bloodstream, followed by tissue deposition—often in vessel walls.

In situ complexes

Antibody binds an antigen previously positioned (“planted”) in a tissue; Complexes form locally.

Slide 42 · Complex deposition is conditional—not automatic

Not all antigen–antibody complexes become pathogenic.

Complex properties and local vascular conditions influence deposition.

Medium-sized complexes may be especially pathogenic in the classic systemic model.

Renal and synovial filtration conditions help explain target-organ patterns.

Slide 43 · Type III frequently affects filtration interfaces

Glomeruli

Immune complexes may localize in renal filtering structures and provoke glomerulonephritis.

Synovium and small vessels

Deposition can produce arthritis and vasculitis; Distribution follows hemodynamic and tissue factors.

Slide 44 · Complement recruits tissue-damaging leukocytes

Immune complexes deposit

Complement is activated

Leukocytes are recruited

Enzymes / toxic species released

The inflammatory response, rather than simple antibody binding, produces the characteristic lesion.

Slide 45 · Necrotizing vasculitis is a Type III pattern

Inflammation with fibrinoid necrosis

Deposited immune complexes and activated inflammatory cells can cause vessel-wall damage; Fibrinoid necrosis is a characteristic morphologic consequence.

Slide 46 · Serum sickness: The systemic prototype

1

Exposure to soluble foreign antigen elicits an antibody response.

2

Circulating antigen–antibody complexes form while antigen persists.

3

Complexes deposit in tissues, activating complement and leukocytes.

4

Fever, urticaria, arthralgia and proteinuria may accompany inflammation.

Slide 47 · Arthus reaction: Localized immune complex injury

Local antigen challenge

Complexes in local vessel walls

Acute vasculitis

Fibrinoid necrosis ± thrombosis

A Type III mechanism can be localized rather than systemic.

Slide 48 · Immune complex disorders can be systemic or focal

Systemic pattern

SLE and serum sickness illustrate persistent or widespread immune complex responses affecting multiple organs.

Tissue-focused pattern

Some glomerulonephritis and Arthus reactions emphasize local sites of deposition and injury.

Slide 49 · Type II versus Type III: Ask where antigen sits

Type II: Fixed target

Antibody binds an antigen intrinsic to or attached to a cell / tissue.

Loss, inflammation or functional disturbance follows.

Type III: Complex deposition

Soluble or locally formed antigen–antibody complexes deposit and recruit inflammation.

Distribution often involves vessels, glomeruli and joints.

Slide 50 · Type IV hypersensitivity is T-cell mediated

CD4+ inflammation or CD8+ target-cell killing

T lymphocytes—not deposited immune complexes or mast-cell IgE—are the defining pathogenic effectors.

Slide 51 · Type IV branches into inflammation and cytotoxicity

Antigen recognized by sensitized T cell

CD4+ Th1 / Th17 cytokines

CD8+ cytotoxic T cells

Macrophage / leukocyte inflammation

Direct target-cell killing

Slide 52 · Th1 cells promote macrophage-dominated injury

Antigen-presenting cell

CD4+ Th1 activation

IFN-γ production

Macrophage activation

Persistent macrophage-rich inflammation can become tissue destructive.

Slide 53 · Th17 responses preferentially recruit neutrophils

Inflammatory priming of CD4+ cells

Th17 differentiation

Neutrophil-rich response

Inflammatory tissue damage

Type IV is not restricted to mononuclear infiltrates; Th17 responses add neutrophils.

Slide 54 · CD8+ cytotoxic lymphocytes destroy target cells

Intracellular peptide antigen

Recognition by CD8+ T cell

Cytotoxic effector response

Target-cell death

This arm can dominate in selected autoimmune and virus-associated injury patterns.

Slide 55 · Delayed-type hypersensitivity is a Type IV prototype

Clinical time course

A previously sensitized person develops a detectable skin response after antigen challenge, typically in 24–48 hours.

Mechanistic substrate

Antigen-specific T cells produce cytokines that recruit and activate inflammatory cells.

The “delay” reflects a cellular response.

Slide 56 · Type IV generates different tissue patterns

Cytokine-mediated reaction

Perivascular infiltrates, tissue edema and chronic inflammatory injury; Macrophage activation may produce granulomas.

Cytotoxic reaction

Direct target-cell destruction by antigen-specific CD8+ T lymphocytes; Organ dysfunction follows cell loss.

Slide 57 · Type IV prototypes represent different T-cell effects

Prototype

Primary tissue manifestation

Characteristic response

Contact dermatitis

Cutaneous cellular inflammation

Delayed T-cell skin reaction

Tuberculosis

Cell-mediated chronic inflammation

Granulomatous immune response

Type 1 diabetes

Islet-cell injury

T-cell-associated cell destruction

Multiple sclerosis

CNS inflammatory demyelination

T-cell-associated immune injury

Slide 58 · Granulomas can result from persistent T-cell activation

Macrophage accumulation and organization

Some Type IV responses become granulomatous when cytokine-driven macrophage activation persists, as in tuberculosis. Granulomas are not obligatory in every Type IV disease.

Slide 59 · Type IV differs from the antibody-associated classes

Primary effector

Antigen-specific CD4+ / CD8+ T lymphocytes and their cytokine or cytotoxic programs.

Typical pathology

Cellular inflammation, macrophage activation, granulomas or direct parenchymal cell destruction.

Slide 60 · Diagnostic morphology: Compare the likely lesion

Type

Pathologic clue

How to interpret it

I

Edema, mucus, eosinophilic inflammation

Mediator-induced tissue reactions

II

Cell loss, tissue inflammation or normal morphology despite dysfunction

Direct target-specific antibody effects

III

Vascular inflammation, fibrinoid necrosis

Deposited complex-triggered inflammation

IV

Cellular infiltrates, granulomas, cell death

T-cell cytokines and cytotoxicity

Slide 61 · Mechanistic classification: A practical reasoning tree

What is the dominant immune effector?

Antibody-associated / mast-cell pathways

Antigen-specific T cells

IgE + mast cells

Type I

Target-bound antibody

Type II

Deposited immune complexes

Type III

T-cell inflammatory / cytotoxic

Type IV

Dominant mechanism guides classification; Individual diseases may show overlap.

Slide 62 · Applied case: Abrupt systemic allergic response

Clinical vignette

Minutes after a relevant exposure, a sensitized patient develops urticaria, bronchospasm and hypotension.

Decisive mechanistic clues

Rapid onset; Vascular leakage; Airway smooth-muscle contraction.

Classification and justification

Type I. IgE-bound mast cells release mediators that affect vessels and smooth muscle.

Slide 63 · Applied case: Antibody-directed cell clearance

Clinical vignette

A patient develops hemolysis associated with antibodies recognizing erythrocyte surface antigens.

Decisive mechanistic clues

Target antigen resides on the red cell; Coated circulating cells are removed.

Classification and justification

Type II. IgG and/or complement opsonization promotes RBC destruction.

Slide 64 · Applied case: Immune complex–associated nephritis

Clinical vignette

A patient with a compatible systemic immune response develops glomerular inflammation and immune complex deposition.

Decisive mechanistic clues

Antigen–antibody complexes localize in glomeruli and recruit inflammation.

Classification and justification

Type III. Deposited complexes activate complement and inflammatory leukocytes.

Slide 65 · Applied case: Delayed contact reaction

Clinical vignette

A previously sensitized patient develops an inflamed skin lesion a day or two after renewed contact with an antigen.

Decisive mechanistic clues

Delayed cellular inflammatory reaction; Antigen-specific T-cell effectors.

Classification and justification

Type IV. Sensitized T lymphocytes generate a delayed inflammatory response.

Slide 66 · One disorder may recruit several hypersensitivity pathways

The four classes are explanatory models

That multiple immune mechanisms can operate in a single disease. Classification should identify the dominant demonstrated pathway rather than enforce artificial exclusivity.

Slide 67 · Final synthesis: Effector, lesion and prototype

Class

Key effector

Signature lesion

Illustrative disorder

I

IgE / mast cells

Edema + smooth-muscle effects

Anaphylaxis / atopy

II

Target-specific IgG (± IgM)

Cell loss / inflammation / dysfunction

Hemolytic anemia / Graves

III

Deposited IgG complexes

Complement-mediated inflammation

SLE / serum sickness

IV

CD4+ / CD8+ T cells

Cellular inflammation / cell killing

Contact dermatitis / TB

Slide 68 · Four questions to test mechanistic understanding

Is the initiating antibody IgE on mast cells—or does it bind a fixed cellular antigen?

Are antigen–antibody complexes depositing in a tissue rather than binding a fixed target?

Is tissue injury dominated by CD4+ inflammatory responses or CD8+ cytotoxic cells?

Can more than one mechanism plausibly contribute to this disease phenotype?

Slide 69 · Core reference and scope of this lecture

Robbins, Cotran & Kumar

Pathologic Basis of Disease · 11th edition (2026)

Chapter 6: Diseases of the Immune System

Classification and Table 6.1: pp. 181–182; mechanism discussion: pp. 182–190