Allergy pdf

Th2-driven allergic diseases

Chronic inflammatory diseases caused by abnormal immune responses to harmless allergens such as pollen, fungal spores, HDM, and animal dander.

Allergic sensitization

The initial, often symptom-free exposure to an allergen during which allergen-specific Th2 cells are generated.

Aeroallergens

Airborne allergens like pollen, fungal spores, house dust mites, and animal dander capable of inducing respiratory allergies.

Th2 immune response

A type 2-skewed CD4⁺ T cell response characterized by production of IL-4, IL-5, IL-13, and IL-9 leading to IgE class switching, eosinophilia, and mucus production.

Tfh2 cells

produces IL-4, IL-13, and IL-21; they promote IgE/IgG1 class switching and can give rise to effector Th2 cells during allergen re-exposure.

Role of IL-4 in allergy

Cytokine that promotes IgE class switching, Th2 differentiation, and maintenance of the Th2 program.

Role of IL-13 in allergy

Cytokine driving airway hyperreactivity, mucus hypersecretion, and high-affinity IgE generation.

Allergic inflammation hallmarks

Tissue swelling, mucus hypersecretion, airway narrowing, eosinophil infiltration, and bronchial hyperresponsiveness.

Sensitization vs. Challenge phase

Sensitization: initial exposure generating Tfh2 cells; Challenge: subsequent exposures triggering effector Th2 accumulation in lungs and clinical symptoms.

cDC2 (Type-2 conventional dendritic cell)

DC subset specialized in priming Th2 responses; captures allergens and migrates to lymph nodes.

cDC1

DC subset producing high IL-12, promoting Th1 differentiation, and able to suppress Th2 responses.

Signal 1 in T cell priming

Antigen presentation via MHC II leading to TCR recognition.

Signal 2 in T cell priming

Co-stimulation (e.g., CD80/86 → CD28) promoting T cell activation.

Signal 3 in T cell priming

Polarizing cytokines from dendritic cells determining T cell lineage (e.g., IL-12 → Th1).

IL-2's role in Th2 priming

Required for IL-4Rα upregulation, IL-4 responsiveness, and maintenance of early Th2 differentiation.

TLR4 signaling effects

Strong activation → IL-12 production and Th2 suppression; Weak/alternative activation → type-2 inflammation.

LPS (Endotoxin)

Potent TLR4 agonist; high responsiveness suppresses Th2 priming, while low responsiveness can permit Th2 sensitization.

PRR (Pattern Recognition Receptor)

Receptors detecting microbial products; include TLRs, NLRs, CLRs; shape cytokine environment.

Allergen protease activity

Proteolytic components of allergens (e.g., HDM, fungi) that activate epithelial cells and promote Th2 responses.

Epithelial "alarmins"

TSLP, IL-33, IL-25 released from airway epithelium to activate ILC2s and promote Th2 polarization.

ILC2 (Innate Lymphoid Cell 2)

Innate cells activated by alarmins to produce IL-13, enhancing cDC2 migration and Th2 priming.

Transcription factors promoting Th2-skewing DC function

IRF4, KLF4, STAT6 program cDC2 toward low IL-12 production and Th2 promotion.

T-bet in dendritic cells

Required for IL-12 production in cDC2s, enabling suppression of Th2 priming.

IL-12's role in preventing allergy

Drives T-bet expression in T cells, suppressing GATA3 and blocking Th2 differentiation.

GATA3

Master transcription factor for Th2 differentiation; promotes IL-4/IL-5/IL-13 expression.

Bcl6

Transcription factor required for Tfh2 development; represses effector Th2 program.

Blimp-1

Transcription factor required for effector Th2 differentiation during allergen re-exposure.

Tfh2 vs. Th2 fate decision

High Bcl6 → Tfh2; High Blimp-1 → effector Th2; regulated by IL-2, TSLP, IL-33, IL-10.

moDC (Monocyte-derived DC)

Derived from Ly6Chi monocytes when driven by GM-CSF; key sensors of low-dose LPS and producers of TNF-α.

GM-CSF's dual role

Epithelial-derived GM-CSF promotes Th2 sensitization; monocyte-derived GM-CSF promotes moDC differentiation and Th2 suppression.

TNF-α in allergy prevention

Produced by GM-CSF-licensed monocytes; induces T-bet in cDC2s and enhances IL-12 production.

IL-6 in Th2 suppression

Inhibits IL-2 signaling in early T cell activation via SOCS3, independently suppressing Th2 priming.

SOCS3

Negative regulator of cytokine signaling; induced by IL-6 to inhibit IL-2 signaling and Th2 differentiation.

Infant susceptibility to allergy

Infants have reduced TNF-α production, weakened LPS responsiveness, and higher IL-33 activity promoting Th2 bias.

LPS hyporesponsiveness in infancy

Due to lower GM-CSF activity, decreased TLR4/CD14 expression on monocytes, leading to poor IL-12/TNF-α production.

IL-33 hyperactivity in infants

Drives strong ILC2 IL-13 production, promoting Th2-skewing cDC2 activity.

Effect of microbiome on allergy risk

Mature, diverse microbiome increases SCFA production and enhances DC maturation toward Th2-resistant phenotypes.

Short-chain fatty acids (SCFAs)

Microbial metabolites that condition DCs to reduce Th2 responses and support immune homeostasis.

Farm exposure and allergy prevention

High environmental microbial diversity and LPS exposure protect against childhood asthma/allergy.

Particulate matter (PM) and allergy

Air pollutants increase epithelial stress, barrier disruption, and IL-33 release, enhancing Th2 sensitization.

Urban vs. rural allergy risk

Urban environments: low microbial/LPS exposure → higher Th2 sensitization; Rural farms: high LPS → allergy protection.