Sensitization and Activation of Mast Cells

Slide 1 · Sensitization and Activationof Mast Cells

Type I hypersensitivity: from IgE sensitization to tissue responses

Type 2 immunity

IgE–FcεRI

Antigen cross-linking

Mediator release

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain how type 2 immunity generates IgE and sensitizes tissue mast cells.

Describe FcεRI binding, multivalent-antigen cross-linking and activation.

Distinguish degranulation, lipid synthesis and cytokine production.

Connect mast-cell activation to immediate, late-phase and non-IgE responses.

Slide 3 · Immediate hypersensitivity depends on a sensitized host

Allergen

Type 2 response

IgE production

Sensitized mast cell

Reexposure

Allergen exposure may initiate type 2 immune responses and IgE synthesis.

IgE attaches to tissue mast cells before the eliciting encounter.

Reexposure activates these cells and produces rapid tissue effects.

Slide 4 · Sensitization and activation are different events

Sensitization

IgE binding produces a mast cell prepared to recognize its specific antigen.

Activation

Antigen-mediated receptor cross-linking initiates cellular responses.

Sensitization: FcεRI on mast cells becomes occupied by IgE.

Activation: The relevant allergen cross-links cell-bound IgE–FcεRI complexes.

Only activation initiates the mediator-release program described here.

Slide 5 · Mast cells are strategically distributed sentinels

Mast cells derive from the bone marrow and reside widely in tissues.

They are abundant near small vessels, nerves and subepithelial surfaces.

This positioning helps explain rapid local vascular and mucosal reactions.

Mucosal epithelium

Nerve

Small blood vessel

Schematic: Subepithelial tissue

Slide 6 · Perivascular mast cells can rapidly affect vascular function

Mediator release beside vessels

Leads to

Vasodilation and vascular leakage

Mast cells lie near small blood vessels, placing released mediators close to vascular targets.

Increased vascular permeability produces local tissue edema.

Vasodilation contributes to congestion in immediate reactions.

Slide 7 · Subepithelial location supports mucosal reactions

Subepithelial mast cells are positioned close to environmental entry surfaces.

Activated mast cells can alter secretory and smooth-muscle responses.

Tissue location influences the clinical pattern of local allergy.

Mucosal epithelium

Nerve

Small blood vessel

Schematic: Subepithelial tissue

Slide 8 · The mast cell granule is a preformed mediator store

Membrane-bound cytoplasmic granules contain biologically active mediators.

Preformed contents can be released quickly once activation occurs.

Degranulation differs from subsequent synthesis of lipid mediators and cytokines.

Mast cell

Original schematic—not histology

Slide 9 · Acidic granule proteoglycans explain toluidine blue staining

Acidic granule proteoglycans

Leads to

Binding of basic dyes such as toluidine blue

Granules contain acidic proteoglycans with affinity for basic dyes.

Toluidine blue can demonstrate the granule-rich cytoplasm.

This is a cellular staining property—not evidence of antigen specificity.

Slide 10 · Mast cells and basophils share functional features

Feature

Mast cell

Basophil

Usual location

Resident in tissues

Circulates in blood

IgE receptors

FcεRI present

FcεRI present

Granules

Present

Present

Inflammatory sites

Already resident

Can be recruited

Their principal normal anatomic compartments differ.

Slide 11 · Basophils are recruited from the circulation

Blood basophil

Inflammatory recruitment

Entry into tissue

Local effector activity

Basophils are present in small numbers in circulating blood.

Unlike mast cells, they are not normally resident tissue cells.

They may be recruited to an inflammatory site like other granulocytes.

Slide 12 · Sensitization begins with recognition of an allergen

Environmental allergen

Antigen capture

Helper T-cell response

IgE synthesis

Only some environmental antigens elicit a sufficiently strong type 2 response to act as allergens.

Antigen captured at a barrier can initiate helper T-cell responses.

The allergen-specific response precedes mast-cell sensitization.

Slide 13 · Epithelial injury provides type 2–promoting signals

Barrier response

Damaged epithelium releases IL-25, IL-33 and TSLP.

Immune consequence

Signals contribute to the generation of type 2 immune responses.

Injured epithelial cells can produce IL-25, IL-33 and TSLP.

These cytokines favor type 2 responses following exposure to some environmental antigens.

The epithelial barrier therefore contributes actively to immune sensitization.

Slide 14 · Dendritic cells link the barrier to lymphoid tissue

Barrier allergen

Dendritic-cell capture

Draining lymph node

Naive CD4+ T cell

Dendritic cells capture antigens from their site of entry.

They transport captured antigens to draining lymph nodes.

Antigen presentation to naive CD4+ T cells begins adaptive sensitization.

Slide 15 · Naive CD4+ T cells enter type 2 differentiation

Naive CD4+ T cell

Type 2 differentiation

Th2 in tissues

Tfh in node

Antigen presentation and epithelial cytokine signals promote Th2-type responses.

Th2 cells migrate into peripheral tissues to participate in local inflammation.

Related Tfh cells remain within lymphoid tissue and support B cells.

Slide 16 · Tfh and Th2 cells act in different compartments

Cell population

Predominant context

Relevant action

Tfh

Lymphoid organs

IL-4 / IL-13 support IgE switching

Th2

Peripheral tissues

IL-5 supports eosinophils

Th2

Mucosal tissue

IL-13 supports mucus secretion

Tfh cells in lymph nodes help B cells switch to IgE production.

Th2 cells at tissue sites promote eosinophil activation and mucosal responses.

Both are contributors to the coordinated type 2 allergic response.

Slide 17 · IL-4 and IL-13 support IgE class switching

Tfh cytokines

B-cell response

IgE class switching

IgE secretion

Tfh-derived IL-4 and IL-13 act on B cells in lymphoid organs.

These signals promote isotype switching to IgE.

The resulting IgE provides antigen recognition capacity to mast cells.

Slide 18 · IgE-producing plasma cells supply sensitizing antibody

B cell

IgE class switch

IgE plasma cell

Circulating IgE

B-cell differentiation yields plasma cells that secrete IgE.

The antigen specificity of the IgE comes from the adaptive B-cell response.

IgE can subsequently attach to FcεRI on mast cells.

Slide 19 · FcεRI is the high-affinity receptor for IgE

FcεRI recognizes the Fc portion of IgE.

Mast cells and basophils express this receptor at their surfaces.

High-affinity binding lets IgE arm cells for subsequent antigen encounters.

FcεRI

FcεRI

IgE binds; Receptors are not cross-linked

Schematic

Slide 20 · IgE binds by Fc while Fab remains antigen-facing

The IgE Fc portion binds the high-affinity receptor on the cell surface.

The antigen-binding ends remain positioned to encounter allergen.

This arrangement couples antibody specificity to mast-cell activation.

FcεRI

FcεRI

IgE binds; Receptors are not cross-linked

Schematic

Slide 21 · An IgE-coated mast cell is sensitized—not necessarily activated

Surface occupancy of FcεRI by IgE is termed sensitization.

The sensitized cell is poised to react if the corresponding antigen returns.

Antigen-mediated receptor cross-linking is the initiating event for activation.

FcεRI

FcεRI

IgE binds; Receptors are not cross-linked

Schematic

Slide 22 · First exposure establishes immune recognition and preparedness

First exposure

Type 2 priming

IgE production

B-cell class switching

FcεRI loading

Mast cell sensitized

Later encounter

Antigen challenge

The initial allergen encounter induces helper T-cell and B-cell responses.

IgE synthesis and receptor binding occur during sensitization.

The full immediate response is triggered when antigen subsequently activates sensitized cells.

Slide 23 · Sensitization links systemic immunity to local effector sites

Lymph-node IgE

IgE distribution

Tissue FcεRI binding

Site-specific response

IgE is generated through lymphoid immune responses.

Receptor-bound IgE arms mast cells embedded within diverse tissues.

The same type of antigen challenge can yield different symptoms across organs.

Slide 24 · Reexposure initiates recognition on the mast-cell membrane

The triggering antigen binds IgE that is already attached to FcεRI.

The allergen must bring adjacent IgE molecules together for the described activation process.

Recognition is translated into receptor clustering and signal initiation.

FcεRI

FcεRI

Allergen

Adjacent IgE–FcεRI complexes linked

Schematic

Slide 25 · A multivalent allergen cross-links adjacent IgE molecules

A multivalent antigen can engage more than one surface-bound IgE molecule.

This links their underlying FcεRI receptors.

Receptor proximity initiates activation signals inside the mast cell.

FcεRI

FcεRI

Allergen

Adjacent IgE–FcεRI complexes linked

Schematic

Slide 26 · Cross-linking is the key transition to activation

Antigen binds

Adjacent IgE linked

FcεRI grouped

Signaling begins

Antigen bridges neighboring IgE–receptor complexes.

The associated Fc receptors are brought together at the membrane.

Signal transduction follows from the receptor cytoplasmic regions.

Slide 27 · Receptor signaling coordinates more than one effector pathway

Immediate discharge

Preformed granule mediators

New lipid products

Membrane-derived inflammatory mediators

Cytokine program

Recruitment and sustained inflammation

Signals initiated at FcεRI induce release of stored granule contents.

Additional signaling promotes synthesis of new lipid mediators.

Activation also promotes cytokine production and the late-phase response.

Slide 28 · Granule discharge releases preformed mediators

Degranulation rapidly transfers stored mediators to extracellular tissue.

Histamine and proteases are among the important granule products.

This branch helps initiate the earliest vascular and smooth-muscle responses.

Activated mast cell

Original schematic—not histology

Slide 29 · Mediator synthesis begins after cellular activation

FcεRI signaling

Phospholipase A2

Arachidonic acid

Leukotrienes / PGD2

Mast-cell activation initiates generation of newly synthesized lipid mediators.

Phospholipase A2 converts membrane phospholipids to arachidonic acid.

Downstream leukotrienes and prostaglandins contribute to tissue effects.

Slide 30 · Cytokine production sustains the inflammatory cascade

Mast-cell activation

Cytokine release

Leukocyte recruitment

Tissue inflammation

Activated mast cells synthesize cytokines and chemokines.

Mediators including TNF, IL-1 and chemokines promote recruitment of leukocytes.

The inflammatory-cell influx contributes to the late-phase reaction.

Slide 31 · Mast-cell activation has three major outputs

Preformed

Histamine, proteases and proteoglycans

Lipid-derived

Leukotrienes and prostaglandin D2

Transcriptional

Cytokines and chemokines

Stored granule contents act rapidly.

Newly formed lipid mediators amplify vasoactive and bronchial responses.

Cytokines and chemokines connect the trigger to later inflammation.

Slide 32 · Immediate reactions typically emerge within minutes

Exposure

Sensitized host

Minutes

Vascular / smooth-muscle response

Hours

Immediate response subsides

The immediate phase is rapid after allergen challenge in a sensitized individual.

It features vasodilation, vascular leakage and tissue-dependent smooth-muscle or secretory effects.

These responses often diminish over the following hours.

Slide 33 · Late-phase reactions can follow without another exposure

Allergen challenge

Initiating event

Minutes

Immediate response

2–24 hours

Late-phase inflammation

Days

Possible persistence

A second inflammatory response may begin 2–24 hours after challenge.

Additional allergen exposure is not required for this subsequent phase.

Leukocyte influx and epithelial damage can maintain symptoms for days.

Slide 34 · Local hypersensitivity can become chronic inflammation

Repeated exposure

Mast-cell activation

Leukocyte influx

Ongoing inflammation

Recurrent exposures generate repeated immediate and delayed episodes.

Recruited inflammatory cells produce additional cytokines and other mediators.

The resulting disease may be chronic despite a rapidly triggered initiating mechanism.

Slide 35 · IgE is not the only route to mast-cell activation

IgE dependent

Allergen cross-links FcεRI-bound IgE.

IgE independent

Other stimuli directly or indirectly activate mast cells.

Some mast-cell triggers do not require allergen–IgE cross-linking.

Complement products, certain drugs, signaling molecules and physical conditions are described activators.

These pathways can produce reactions resembling immediate hypersensitivity.

Slide 36 · Complement anaphylatoxins can activate mast cells

Complement activation

C3a / C5a

Mast-cell receptors

Mediator release

C3a and C5a are designated anaphylatoxins.

They can act through receptors on mast-cell membranes.

Their effects may mimic some manifestations of anaphylaxis without the IgE cross-linking sequence.

Slide 37 · Certain drugs can act as alternative mast-cell stimuli

Drug exposure (examples: Codeine, morphine)

Leads to

Possible mast-cell activation without IgE cross-linking

Codeine and morphine among agents that can activate mast cells.

This mechanism is distinct from the classic allergen-mediated IgE cross-linking sequence.

A drug-associated immediate reaction does not by itself prove antigen-specific IgE.

Slide 38 · Adenosine, chemokines and venom components are additional triggers

Adenosine

Non-antigenic chemical stimulus

IL-8

Chemokine named as an activator

Melittin

Bee-venom component

The text lists adenosine and IL-8 among mast-cell activators.

Melittin, a component of bee venom, is also included.

These examples illustrate the diversity of mast-cell activation signals.

Slide 39 · Physical stimuli may activate mast cells

Heat

Physical stimulus

Cold

Physical stimulus

Sunlight

Physical stimulus

Heat and cold are listed physical triggers.

Sunlight is another reported physical stimulus.

Recognizing this group helps separate antigen-specific sensitization from stimulus-triggered activation.

Slide 40 · IgE and non-IgE triggers must not be conflated

Feature

IgE-dependent route

Other mast-cell triggers

Preparation

Prior IgE sensitization

No required IgE priming

Initiator

Relevant multivalent allergen

Complement, drugs, physical factors

Key step

IgE–FcεRI cross-linking

Other membrane/stimulus pathways

Common endpoint

Mediator release

Mediator release

Both converge on mast-cell mediator release and overlapping manifestations.

Slide 41 · Mediators account for the outward manifestations of activation

Vessels

Dilation and increased permeability

Smooth muscle

Contraction and spasm

Glands / mucosa

Increased secretions

Mast-cell mediators influence vessels, smooth muscle and glands.

Some initiate rapid symptoms; Others recruit inflammatory cells.

The local tissue response depends on where mast cells are activated.

Slide 42 · Histamine is a major rapid granule mediator

Mast-cell granule

Histamine release

Vascular / muscle / gland effects

Histamine is stored as a vasoactive amine within mast-cell granules.

It increases vascular permeability and contracts smooth muscle.

It also stimulates secretion from nasal, bronchial and gastric glands.

Slide 43 · Mast-cell proteases can promote tissue injury

Granule proteases

Local substrate cleavage

Tissue injury / new mediator generation

Granule enzymes include tryptase, chymase and acid hydrolases.

These enzymes can damage tissue and act on precursor proteins.

Some downstream products include kinins and complement components.

Slide 44 · Granule proteoglycans help package stored mediators

Proteoglycan-rich granule matrix

Leads to

Storage of amines + affinity for basic dyes

Heparin and chondroitin sulfate are cited proteoglycans.

They aid storage and packaging of the granule amines.

Their acidic chemistry also explains affinity for basic stains.

Slide 45 · Arachidonic-acid metabolism yields new lipid mediators

Membrane lipids

Arachidonic acid

5-lipoxygenase / COX

Leukotrienes / prostaglandins

Mast-cell activation stimulates phospholipase A2 activity.

Membrane phospholipids yield arachidonic acid.

Lipoxygenase and cyclooxygenase pathways generate distinct mediator families.

Slide 46 · LTC4 and LTD4 intensify vasoactive and spasmogenic effects

Newly generated LTC4 and LTD4

Leads to

Vascular leakage + bronchial constriction

Leukotrienes C4 and D4 are potent vasoactive and spasmogenic agents.

They increase vascular permeability and contract bronchial smooth muscle.

These actions reinforce acute airway and vascular reactions.

Slide 47 · LTB4 has a different principal inflammatory role

Mast-cell LTB4

Leukocyte chemotaxis

Inflammatory-cell accumulation

Leukotriene B4 is chemotactic for inflammatory leukocytes.

Neutrophils, eosinophils and monocytes as responsive cells.

Its role links lipid mediator production to cellular recruitment.

Slide 48 · Prostaglandin D2 contributes to bronchial responses

COX pathway → prostaglandin D2

Leads to

Bronchospasm + mucus secretion

Prostaglandin D2 is the prominent mast-cell cyclooxygenase product described.

It causes intense bronchospasm.

It also increases mucus secretion.

Slide 49 · Mast-cell cytokines recruit and amplify inflammatory cells

Mast-cell cytokines

Leukocyte recruitment

More local mediators

Amplified inflammation

TNF, IL-1 and chemokines contribute to leukocyte recruitment.

IL-4 can amplify the type 2 helper-T-cell response.

Recruited leukocytes provide further sources of cytokines.

Slide 50 · Vascular edema arises from altered vessel permeability

Mediator-driven vascular leakage

Leads to

Interstitial fluid accumulation → edema

Released mediators act on nearby microvasculature.

Vascular leakage causes movement of fluid into surrounding tissue.

This process helps explain swelling in immediate reactions.

Slide 51 · Smooth-muscle spasm underlies important airway effects

Histamine / lipid mediators

Leads to

Bronchial smooth-muscle contraction

Mast-cell mediators can cause intense bronchial smooth-muscle contraction.

Bronchial narrowing contributes to airflow obstruction.

The mechanism is particularly relevant to immediate allergic airway reactions.

Slide 52 · Mucus secretion is another direct tissue response

Rapid effect

Histamine acts on secretory tissues.

Type 2 support

IL-13 enhances epithelial mucus output.

Histamine can increase glandular secretion.

IL-13 from type 2 responses also stimulates epithelial mucus production.

Mucosal hypersecretion contributes to symptoms in allergic airways.

Slide 53 · The late phase is a recruited-cell inflammatory response

Early mediators

Chemokines / cytokines

Leukocyte influx

Tissue injury

Eosinophils, neutrophils and T cells can enter affected tissue.

Mast-cell cytokines and other local signals promote recruitment.

Inflammatory cells contribute further mediators and epithelial injury.

Slide 54 · IL-5 and eosinophils strengthen allergic tissue injury

Th2-derived IL-5

Eosinophil activation

Granule proteins / enzymes

Tissue damage

IL-5 is a major eosinophil-activating type 2 cytokine.

Eosinophils contribute proteolytic enzymes and toxic granule proteins.

This effector axis helps sustain the late inflammatory phase.

Slide 55 · The tissue pattern differs between immediate and late phases

Feature

Immediate phase

Late phase

Typical onset

Minutes after challenge

2–24 hours later

Prominent response

Vascular / smooth-muscle / secretory

Leukocyte-rich inflammation

Tissue features

Congestion and edema

Eosinophils, other leukocytes; Epithelial injury

Immediate lesions emphasize congestion, edema and smooth-muscle effects.

Late lesions emphasize inflammatory cellular infiltration and epithelial damage.

These phases can overlap clinically.

Slide 56 · Allergic rhinitis illustrates a mucosal immediate response

Activation at nasal mucosa

Leads to

Secretions, swelling and inflammation

Local allergen challenge can cause nasal discharge and secretions.

Histamine contributes to rapid glandular and vascular effects.

Subsequent inflammation may sustain symptoms after the initial reaction.

Slide 57 · Asthma illustrates immediate and late-phase mechanisms

Immediate

Bronchial smooth-muscle constriction

Late

Inflammatory infiltration and epithelial injury

Early bronchial smooth-muscle contraction produces airflow obstruction.

Late inflammatory-cell recruitment contributes tissue injury and sustained symptoms.

These overlapping components explain why not all symptoms are purely histamine-mediated.

Slide 58 · Systemic anaphylaxis shows the consequence of widespread activation

Systemic antigen exposure

Widespread mast-cell activation

Vascular / airway effects

Anaphylactic syndrome

Systemic immediate hypersensitivity can produce widespread edema.

Vascular dilation may lead to shock; Airway compromise may accompany laryngeal edema or bronchospasm.

The triggering event can be sudden in a sensitized individual.

Slide 59 · The site of allergen entry shapes the clinical syndrome

Site

Typical tissue effect

Skin

Localized rash, hives or edema

Upper airway

Rhinitis with increased secretions

Bronchi

Airway smooth-muscle constriction

Intestine

Smooth-muscle contraction / increased peristalsis

The same basic cellular mechanism therefore produces heterogeneous clinical presentations.

Slide 60 · Case application: Why can repeat exposure cause hives?

Prior sensitization

Allergen reexposure

Cross-linking

Vascular leakage

A previously sensitized individual encounters the relevant allergen again.

The antigen bridges adjacent IgE–FcεRI complexes on tissue mast cells.

Rapid mediator release increases local vessel permeability and generates edema.

Slide 61 · Case application: A rapid reaction without demonstrated IgE

Observation

Supported interpretation

Rapid onset

Compatible with mast-cell mediator effects

Drug / physical trigger

Non-IgE activation is possible

IgE sensitization

Cannot be assumed without evidence

A patient develops flushing-like or immediate symptoms after a listed non-IgE trigger.

Mast-cell mediator release can occur independently of classic antigen-specific cross-linking.

The reaction mechanism cannot be inferred solely from its rapid onset.

Slide 62 · Diagnostic reasoning must separate mechanism from phenotype

Phenotype

Vascular, bronchial or secretory response

Mechanism

IgE cross-linking versus alternative activation

Edema, wheeze or secretions indicate effector physiology, not a unique initiating pathway.

IgE-mediated allergy requires antigen-specific sensitization and triggering.

Other mast-cell activators can produce overlapping immediate manifestations.

Slide 63 · A unified model links immunity to immediate tissue effects

Type 2 immunity

IgE / FcεRI

Allergen cross-linking

Mediators

Tissue effects

Tfh / Th2 responses produce an IgE-driven sensitizing environment.

IgE binding to FcεRI establishes mast-cell readiness.

Cross-linking elicits mediators that produce immediate effects and recruit cells.

Slide 64 · Three discriminations organize this topic

Stage

Sensitization ≠ activation

Product

Stored ≠ newly made

Time

Minutes ≠ 2–24 h

First exposure and IgE coating are distinct from receptor cross-linking.

Stored granule contents differ from newly synthesized lipids and cytokines.

An immediate effector response is distinct from later leukocyte-rich inflammation.

Slide 65 · Applied synthesis: Follow the cell from priming to disease

Priming

Tfh / Th2

Arming

IgE–FcεRI

Trigger

Allergen cross-linking

Effector

Mediators

Injury

Immediate ± late phase

An allergen elicits IgE through a type 2 helper-T-cell response.

IgE persists on mast-cell FcεRI, enabling recognition at a future encounter.

Cross-linking triggers early and delayed pathways whose organ-specific effects cause clinical allergy.

Slide 66 · Primary source and terminology

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th edition.

FcεRI: high-affinity IgE Fc receptor on mast cells and basophils.

Tfh: T follicular helper cell; Th2: type 2 helper T cell.

TSLP: thymic stromal lymphopoietin; PGD2: prostaglandin D2.