Development of Allergies

Slide 1 · Development of Allergies

Genetic susceptibility • environment • type 2 immunity • clinical expression

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Define atopy and describe its characteristic clinical phenotypes.

Interpret the genetic and environmental contributions to allergic susceptibility.

Link type 2 immunity and IgE sensitization to clinical reactions.

Distinguish IgE-dependent allergy from nonantigenic mast-cell activation.

Critically interpret the hygiene hypothesis and early allergen exposure.

Slide 3 · Why does an ordinary exposure provoke allergy?

Mechanistic question

Common environmental substances are not inherently dangerous to most people.

Atopic susceptibility favors an exaggerated type 2 response.

Clinical manifestations require activation of tissue effector pathways.

Environmental encounter

Allergen reaches host surfaces

Susceptible immune response

Type 2 immunity and IgE production

Reexposure

Sensitized mast cells release mediators

Organ response

Airway, skin, gut or systemic manifestations

Slide 4 · Atopy is a predisposition, not an acute reaction

Atopy

Inherited propensity to develop allergic disease.

May manifest through several clinical disorders.

Associated with increased serum IgE and IL-4-producing Th2 cells.

Allergic episode

An effector event following activation of relevant inflammatory pathways.

In IgE-mediated allergy, reexposure cross-links mast-cell-bound IgE.

Expression depends on involved tissue and released mediators.

Slide 5 · Principal disorders within the atopic spectrum

Allergic rhinitis

Upper-airway mucus secretion and inflammation after allergen exposure.

Asthma

Bronchial smooth-muscle hyperreactivity; Late inflammatory injury can contribute.

Atopic dermatitis

An atopic inflammatory disorder of the skin.

Food allergy

A food-related allergic phenotype; Intestinal smooth-muscle effects may occur.

Slide 6 · Atopy can affect more than one organ

Multiorgan phenotype

Several atopic disorders often coexist in the same individual.

Different involved organs may generate different symptoms.

A single patient need not have every atopic condition.

Shared atopic susceptibility

Individual predisposition

Upper respiratory tract

Rhinitis

Lower respiratory tract

Asthma

Skin and gut

Dermatitis / food allergy

Slide 7 · The atopic triad

Atopic dermatitis

Cutaneous atopic disease.

Allergic rhinitis

Nasal allergic inflammation.

Asthma

Allergic airway disorder.

Slide 8 · Atopic march: The classical clinical pattern

Characteristic clinical sequence

Infancy

Atopic dermatitis

Later childhood

Allergic rhinitis and / or asthma

This is a descriptive sequence reported in some patients.

The pattern does not establish that dermatitis necessarily causes later asthma.

Slide 9 · What the atopic march does—and does not—mean

What it describes

Atopic dermatitis in infancy followed by later respiratory atopy.

A recognizable sequence of clinical phenotypes.

Potentially more than one atopic disorder in the same individual.

What it does not establish

An inevitable order in all atopic patients.

A proven direct causal chain from one disorder to the next.

A requirement for diagnosis of atopy.

Slide 10 · Atopy is associated with a type 2 immune phenotype

Higher serum IgEMore IL-4–producing Th2 cells

These observations characterize group-level tendencies in atopy.

Neither observation alone establishes a clinical diagnosis of allergy.

Slide 11 · IL-4 links type 2 immunity with IgE

Type 2 axis

Atopic individuals tend to have more IL-4–producing Th2 cells.

The parent mechanism shows type 2 immune help for IgE production.

IgE subsequently sensitizes mast cells through high-affinity receptors.

Type 2 T-cell response

IL-4–associated activity

B-cell response

IgE class switching

Mast-cell binding

IgE attaches to FcεRI

Potential reactivity

Prepared for allergen reexposure

Slide 12 · Familial susceptibility reflects inherited risk

Gene–environment framework

Susceptibility to allergic disease has a genetic component.

The mechanisms underlying familial predisposition remain incompletely understood.

Genetic associations do not fully determine clinical phenotype.

Inherited variants

Host susceptibility

Immune-response tendency

Type 2 / allergen responsiveness

Environmental exposures

Encounter with relevant stimuli

Clinical expression

Possible atopic disease

Slide 13 · Family history is common among atopic individuals

Almost 50%

Almost half of atopic individuals have a positive family history of allergy.

This describes the atopic group; It is not a risk estimate for a person with an affected relative.

Slide 14 · How to interpret the family-history observation

Supported interpretation

Affected relatives provide evidence of familial aggregation.

The observation is compatible with inherited susceptibility.

Family history is informative but not universal in atopy.

Unsupported inference

“Half of all children with an affected parent become allergic.”

“Family history is necessary for atopy.”

“One gene explains all allergic disease.”

Slide 15 · Cytokine-related loci linked to allergic phenotypes

IL-3 / IL-4

Reported linkage to polymorphisms in cytokine-related genes.

IL-5 / IL-9

Additional cytokine loci included in asthma association studies.

IL-13

A cytokine gene within the reported association set.

GM-CSF

GM-CSF is also listed among reported cytokine-related loci.

Slide 16 · Genetic association is not mechanistic proof

The functional effects of the reported polymorphisms remain unclear.

The role of these polymorphisms in allergy development is not yet established.

Linkage identifies an association; It does not by itself reveal biological mechanism.

Slide 17 · HLA variation may influence allergen reactivity

Proposed association

HLA polymorphisms have also been linked to allergic susceptibility.

The HLA region is on chromosome 6.

The suggested implication is inherited responsiveness to particular allergens.

HLA polymorphism

Inherited genetic variation

Antigen recognition context

Possible differences in allergen responsiveness

Susceptible phenotype

Increased potential for allergic sensitization

Slide 18 · Cytokine and HLA associations are distinct

Cytokine-linked loci

Concern mediators that participate in allergic reactions.

Include IL-3, IL-4, IL-5, IL-9, IL-13 and GM-CSF.

Their contribution to the disease phenotype remains mechanistically uncertain.

HLA-linked loci

Located in the chromosome 6 HLA region.

Suggest variation in responsiveness to selected allergens.

Are described as an association, not a deterministic genotype.

Slide 19 · Inherited risk requires environmental context

Integrated model

Genetic susceptibility influences which responses may arise.

Environmental exposures contribute to the development of clinical disease.

Observed allergy reflects both predisposition and effector activation.

Host factors

Atopic tendency / reported loci

Context

Environmental pollutants and other exposures

Immune events

IgE sensitization or nonimmune activation

Manifestation

Organ-specific allergic syndrome

Slide 20 · Environment modifies allergy susceptibility

Allergic disease is not explained by genetic risk alone.

Environmental pollutants are among the factors that predispose to allergy.

It also identifies viral airway infections as triggers of asthma.

Slide 21 · Pollutant exposure is a predisposing influence

Environmental susceptibility

Environmental pollutants are particularly relevant in industrialized settings.

Pollutant exposure is associated with predisposition to allergic disease.

A predisposing association does not specify an individual risk magnitude.

Industrialized environment

Potential pollutant exposure

Predisposing influence

Greater allergic susceptibility

Possible clinical disease

Dependent on host and other exposures

Slide 22 · Respiratory viruses can trigger asthma

Trigger vs predisposition

Viral infections of the airways can trigger asthma.

A triggering event is not the same as establishing inherited atopy.

The detailed airway pathology belongs to the respiratory chapter.

At-risk airway

Asthma susceptibility

Viral airway infection

Environmental trigger

Clinical response

Asthma symptoms / exacerbation

Slide 23 · Predisposition and trigger answer different questions

Predisposition

Why a host is susceptible to allergic disease.

Examples: Atopic genetic background and environmental influences.

May exist before symptoms appear.

Trigger

What precipitates a particular episode.

Examples: Allergen reexposure or viral airway infection in asthma.

Does not necessarily explain the underlying susceptibility.

Slide 24 · Allergic disease frequency has increased with urbanization

A population trend does not identify a single cause.

Many allergic diseases have become more frequent in developed countries.

This observation helped motivate the hygiene hypothesis; Causation remains a separate question.

Slide 25 · Different exposures can occupy different roles

Allergens

Environmental antigens that initiate type 2 immunity and IgE sensitization.

Pollutants

Environmental factors described as predisposing to allergic disease.

Airway viruses

Triggers of asthma rather than allergens in the usual IgE pathway.

Temperature / exercise

Nonantigenic stimuli that may evoke immediate hypersensitivity-like events.

Slide 26 · Exposure alone does not define the mechanism

Antigen-dependent pathway

An allergen evokes type 2 immunity and IgE production.

The relevant tissue mast cells become sensitized.

Repeated antigen exposure can trigger receptor cross-linking.

Antigen-independent pathway

Some immediate reactions follow physical or other nonantigenic stimuli.

This subset does not require Th2 cells or IgE.

Mast-cell hypersensitivity to nonimmune stimuli is proposed.

Slide 27 · Epithelial tissues participate in type 2 responses

Mucosal interface

Mucosal tissues are an important interface for encountered allergens.

Epithelial signals include IL-25, IL-33 and TSLP.

These signals participate in the initiation of type 2 responses.

External allergen

Exposure at a mucosal surface

Epithelial signals

IL-25 · IL-33 · TSLP

Immune activation

Type 2 response

Effector outcome

IgE / mast-cell sensitization

Slide 28 · First exposure creates allergic sensitization

Sensitization sequence

The parent section distinguishes first exposure from repeat encounter.

Initial immune activation includes T-cell help and IgE class switching.

IgE binds to high-affinity mast-cell FcεRI receptors.

First encounter

Allergen presented to immune system

Tfh and Th2 response

Support for IgE-producing B cells

IgE production

Plasma-cell output

Mast-cell sensitization

FcεRI occupancy

Slide 29 · Tfh and Th2 cells have complementary roles

T follicular helper cells

Provide B-cell help in lymphoid organs.

IL-4– and IL-13–producing Tfh cells are part of the depicted pathway.

Contribute to IgE class switching.

Th2 cells

Contribute to type 2 cytokine responses in tissues.

Atopic individuals tend to have more IL-4-producing Th2 cells.

Help sustain eosinophilic inflammation.

Slide 30 · IgE production makes allergen recognition actionable

IgE effector link

Antigen-specific IgE is generated with appropriate T-cell help.

IgE becomes attached to FcεRI on mast cells.

Sensitized cells can respond rapidly during subsequent antigen exposure.

B-cell class switching

IgE-producing response

Circulating IgE

Specific binding to FcεRI

Resident mast cell

IgE is retained at tissue interface

Slide 31 · Tissue mast cells are strategically located

Anatomical distribution

Mast cells derive from bone marrow but reside widely in tissues.

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

This distribution helps explain local vascular and mucosal reactions.

Subepithelial mast cell

Local effector cell

Nearby microvessels

Vascular leakage / edema

Nearby smooth muscle

Spasm / airflow effects

Slide 32 · Repeat exposure cross-links mast-cell IgE

Activation sequence

Multivalent antigen can bind adjacent cell-surface IgE molecules.

FcεRI receptor clustering triggers intracellular activation.

Preformed and newly synthesized mediators are then released.

Prior sensitization

IgE already bound to FcεRI

Repeat allergen

Cross-links neighboring IgE

Mast-cell activation

Degranulation and mediator synthesis

Clinical reaction

Immediate and subsequent late phase

Slide 33 · The allergic effector response has two phases

Temporal organization of type I hypersensitivity

Minutes

Immediate vascular and smooth-muscle response

2–24 hours

Late inflammatory cellular response

Both phases can follow a single allergen encounter in a sensitized host.

Late inflammation can persist without a second exposure to the antigen.

Slide 34 · Preformed mast-cell mediators act rapidly

Histamine

Vascular permeability, smooth-muscle contraction, mucus secretion.

Neutral proteases

Tryptase and chymase participate in tissue effects.

Acid hydrolases

Included in granule contents and contribute to tissue injury.

Granule proteoglycans

Heparin and chondroitin sulfate store and package amines.

Slide 35 · Newly synthesized lipid mediators extend the response

Leukotrienes C₄ / D₄

Strong vascular and bronchial smooth-muscle effects.

Leukotriene B₄

Chemotactic activity for leukocyte populations.

Prostaglandin D₂

Bronchospasm and increased mucus secretion.

Arachidonic-acid pathway

Substrate pathway giving rise to prostaglandins and leukotrienes.

Slide 36 · Mast-cell cytokines recruit a late infiltrate

Late-phase cascade

Mast cells produce TNF, IL-1 and chemokines.

These promote recruitment of leukocytes into affected tissue.

Inflammatory cells amplify mediator release and may injure epithelium.

Mast-cell activation

TNF · IL-1 · chemokines

Leukocyte recruitment

Inflammatory infiltrate

Further mediators

Amplified inflammatory activity

Tissue response

Epithelial damage / sustained symptoms

Slide 37 · Eosinophils contribute to tissue injury

Eosinophil contribution

IL-5 strongly activates eosinophils.

Eosinophils release proteolytic proteins including major basic protein.

These products contribute to epithelial damage in late reactions.

Th2-associated cytokines

IL-5

Activated eosinophil

Granule protein release

Epithelial injury

Sustained late-phase inflammation

Slide 38 · Immediate and late tissue effects are different

Early phase

Vasodilation, vascular leakage and edema.

Contraction of smooth muscle.

Mucus secretion.

Late phase

Inflammatory infiltrate with eosinophils and other leukocytes.

Additional mediator production.

Epithelial damage and sustained inflammation.

Slide 39 · Tissue effects translate into distinct symptoms

Nose / sinuses

Mucus secretion and upper-airway inflammation.

Bronchi

Airway narrowing from smooth-muscle effects and inflammation.

Gut

Altered peristalsis linked to intestinal muscle contraction.

Systemic vessels / larynx

Vasodilation and edema can produce shock or airway compromise.

Slide 40 · In asthma, late inflammation may dominate symptoms

Mast-cell activation is only the beginning.

Late-phase inflammation contributes substantially to some allergic asthma presentations.

This explains why reducing inflammation can matter beyond blocking immediate histamine effects.

Slide 41 · Why patients can present with different organ patterns

Shared upstream pathway

Atopic susceptibility can support allergen-driven type 2 immunity.

IgE sensitization and mast-cell mediator release are recurring mechanisms.

Common underlying mechanism does not imply a single clinical presentation.

Different clinical expressions

Nasal glands: Mucus and inflammation.

Bronchial muscle: Airway narrowing.

Skin and gut: Other atopic clinical phenotypes.

Slide 42 · Not all immediate hypersensitivity-like reactions are IgE-mediated

The initiating stimulus may be nonantigenic.

A subset of immediate reactions can be triggered by temperature extremes or exercise.

These events are sometimes described as nonatopic allergy.

Slide 43 · Estimated frequency of nonantigenic immediate reactions

20%–30% of immediate hypersensitivity reactions

This estimate concerns immediate reactions induced by nonantigenic stimuli.

It is not the population prevalence of allergic disease.

Slide 44 · Atopic versus nonatopic immediate reactions

Atopic / classic type I

Allergen-specific type 2 T-cell response.

IgE class switching and FcεRI sensitization.

Reexposure cross-links mast-cell-bound IgE.

Nonatopic / nonantigenic

Trigger can be a temperature change or exercise.

No Th2 or IgE requirement in the described subgroup.

Abnormal mast-cell responsiveness is proposed.

Slide 45 · Physical stimuli may activate mast cells

Heat

A potential direct physical trigger.

Cold

A physical stimulus that can activate mast cells.

Sunlight

Included among stimuli activating mast cells in parent section.

Exercise

Named as a nonantigenic trigger of immediate reactions.

Slide 46 · Other mast-cell activation routes

Complement C3a / C5a

Anaphylatoxins can activate mast cells through their receptors.

Codeine / morphine

Drugs listed among possible mast-cell activators.

Adenosine / chemokines

Additional reported mast-cell activating stimuli.

Bee venom melittin

A non-IgE activating stimulus discussed in parent section.

Slide 47 · Nonatopic reactions suggest altered effector sensitivity

Proposed mechanism

Unusual mast-cell responsiveness to nonimmune stimuli is proposed.

This is a hypothesis for the mechanism, not a complete causal explanation.

The clinical endpoint can resemble IgE-dependent mediator effects.

Nonimmune stimulus

Physical or pharmacologic input

Mast-cell activation

Proposed increased sensitivity

Mediator effects

Edema / spasm / secretion

Slide 48 · Similar symptoms need not imply the same pathogenesis

Shared effector result

Mast-cell mediator release can cause vascular and smooth-muscle changes.

A clinical pattern alone may not identify the initiating route.

Anaphylaxis-like physiology is not itself proof of antigen-specific IgE.

Different initial route

Classic type I: Allergen-specific IgE cross-linking.

Nonantigenic: Mast-cell activation without Th2 / IgE in the described subset.

Complement and selected drugs provide additional activation pathways.

Slide 49 · The hygiene hypothesis arose from a population observation

More allergy in increasingly urbanized, developed settings

The observation motivated a hypothesis about reduced early environmental or microbial exposure.

The hypothesis is explanatory, not proof of a single causal pathway.

Slide 50 · The proposed mechanism is early immune education

Hypothesis; Not proven sequence

Early-life environmental, including microbial, antigen exposure may shape later responsiveness.

The hypothesis includes prenatal and early-childhood windows.

Its proposed effect is reduced later pathological responses to common allergens.

Prenatal / early childhood

Environmental antigen encounters

Immune education

Proposed developmental influence

Later allergen contact

Potentially less pathologic reaction

Slide 51 · Separate observation, hypothesis and evidence

Observations

Allergic diseases increased as developed societies urbanized.

Atopic susceptibility also has genetic associations.

An association does not uniquely identify the responsible exposure.

Explanatory interpretation

Early microbial and environmental encounters may modulate immune development.

Improved early hygiene might reduce protective exposures.

This remains broader than a single experimentally proven mechanism.

Slide 52 · Allergy susceptibility develops across life stages

Timing connects environmental hypotheses to clinical patterns

Prenatal period

Proposed immune education window

Infancy

Early environmental / food encounters

Childhood

Atopic phenotypes may become clinically apparent

The proposed early developmental influence does not imply fixed outcomes.

Atopic march describes one observed clinical pattern, not a mandatory timetable.

Slide 53 · Early peanut exposure is a specific protective example

Specific early-exposure example

Small amounts of peanut-containing foods are given in infancy and early childhood in this example.

Early exposure in the cited example reduces later peanut allergy incidence.

This illustrates that some early exposures may be protective, not invariably sensitizing.

Early peanut-containing foods

Small amounts in early life

Developmental exposure

Context for immune response

Later outcome

Lower peanut allergy incidence in the cited example

Slide 54 · What the peanut example does not establish

What the example supports

Early peanut-containing food exposure can reduce later peanut allergy incidence.

The example is consistent with developmental immune modulation.

Exposure timing matters in the specific example.

What the example cannot establish

Universal benefit of unrestricted allergen exposure.

An unsupervised feeding recommendation for a particular infant.

An identical protective effect for every allergen.

Slide 55 · Allergic rhinitis: Local upper-airway expression

Clinicopathologic link

Environmental allergen exposure can precipitate local immediate hypersensitivity.

Histamine and other mediators drive mucus secretion.

Upper-airway inflammation contributes to symptoms.

Airborne allergen

Upper-airway exposure

Sensitized mast cells

Rapid mediator release

Nasal response

Mucus secretion / inflammation

Slide 56 · Asthma: Airway spasm plus inflammation

Clinicopathologic link

Bronchial smooth-muscle hyperactivity contributes to airway obstruction.

Late eosinophil-rich inflammation can cause injury and sustained symptoms.

Viral airway infections are recognized triggers in susceptible patients.

Susceptible airway

Genetic / atopic context

Triggering event

Allergen or airway infection

Airway consequences

Smooth-muscle response + inflammation

Slide 57 · Atopic dermatitis: Part of the atopic spectrum

Clinical pattern

Atopic dermatitis is one of the most common clinical forms of atopy.

It may be the first disorder in the described atopic march.

Coexistence with later rhinitis or asthma is possible.

Atopic propensity

Shared underlying susceptibility

Skin phenotype

Atopic dermatitis

Potential later findings

Rhinitis and / or asthma

Slide 58 · Food allergy: An atopic phenotype with gut effects

Clinicopathologic link

Food allergy belongs to the spectrum of common atopic disorders.

Intestinal muscle contraction can increase peristalsis during immediate reactions.

Food allergens can also precipitate systemic reactions in sensitized hosts.

Food allergen

Exposure in sensitized host

Mediator effects

Intestinal smooth-muscle response

Clinical range

Local gut symptoms or systemic response

Slide 59 · Local allergy and anaphylaxis differ in severity

Localized presentations

Rhinitis, asthma, dermatitis, food-allergy phenotypes.

Organ-related mucus, smooth-muscle and inflammatory effects.

Can coexist within a single atopic individual.

Systemic anaphylaxis

Potentially widespread vascular leakage and vasodilation.

Edema, bronchospasm and hypotensive shock.

Life-threatening even with very small triggering exposures.

Slide 60 · Clinical reasoning: An evolving atopic phenotype

Clinical scenario

A child has atopic dermatitis in infancy, then develops allergic rhinitis and asthma during childhood.

Reason through the mechanism

What clinical pattern does this illustrate?

Does this history alone prove dermatitis caused asthma?

What shared predisposition connects the disorders?

Slide 61 · Clinical reasoning: An immediate nonantigenic trigger

Clinical scenario

An individual develops an immediate mast-cell–type reaction after a marked temperature change, without an identified allergen exposure.

Reason through the mechanism

Which pathway is suggested by the trigger?

Must allergen-specific IgE necessarily be involved?

Which proposed effector abnormality is relevant?

Slide 62 · Clinical reasoning: Early environmental exposure

Clinical scenario

The frequency of allergy is reported to rise during urbanization, while early exposure to peanut-containing foods is associated with less subsequent peanut allergy.

Reason through the mechanism

Which hypothesis addresses the population pattern?

Which observation is specific to peanut allergy?

Why should the two not be treated as identical evidence?

Slide 63 · Integrated model: From predisposition to manifestations

Inherited susceptibility

Cytokine-related and HLA-associated loci

Environmental context

Pollution, microbial and other encounters

Pathway selection

Type 2 / IgE sensitization or nonantigenic activation

Mast-cell and tissue response

Mediator release with variable organ expression

Clinical spectrum

Rhinitis · asthma · dermatitis · food allergy · anaphylaxis

Slide 64 · Five durable conclusions

Atopy denotes susceptibility; An allergic reaction is an event.

Family and candidate-gene associations indicate risk but not deterministic causation.

Environmental exposures may predispose, trigger, or modify immune development.

IgE-mediated sensitization and nonantigenic mast-cell activation are mechanistically distinct.

Organ phenotype and phase of inflammation determine the clinical presentation.

Slide 65 · Primary reference and contextual sections

Robbins, Cotran & Kumar: Pathologic Basis of Disease

11th edition (2026) — Diseases of the Immune System

Primary focus: Development of Allergies

Mechanistic context: sensitization and activation of mast cells; mediators and late-phase reactions.