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Chapter 14 - Allergy: Basic Mechanisms

Scott-Brown's Otorhinolaryngology Head & Neck Surgery, Vol. 1

Introduction

Allergy is defined as a hypersensitivity reaction initiated by specific immunologic mechanisms. More precisely, it describes objectively reproducible symptoms or signs triggered by exposure to a defined stimulus at a dose that normal (non-atopic) persons tolerate without reaction.

Two terms to distinguish upfront:

Hypersensitivity = an altered immune response to an antigen that causes tissue damage
Allergy = the disease manifestation of sensitization (not everyone who is sensitized becomes symptomatic)

An allergen is an antigen - usually a protein - that causes allergic disease. Inhaled allergens (pollen, house dust mite, mould spores, pet dander, cockroach) are the main drivers of allergic airway diseases like rhinitis.

Atopy is the tendency to become sensitized and produce allergen-specific IgE (sIgE) in response to ordinary everyday exposures. It is confirmed clinically by positive skin prick tests and/or raised serum sIgE to one or more allergens.

Aetiology of Sensitization

Type I (IgE-mediated) hypersensitivity only occurs in a sensitized individual. Sensitization is multifactorial, involving:

Host (Genetic) Factors

Up to 40% of people in industrialized countries carry atopic tendency. An atopic person typically has:

Elevated total IgE
Strong family history of allergic disease
Increased susceptibility to allergic rhinitis, asthma, and atopic dermatitis

Key genetic loci associated with allergic disease include:

Chromosome 11q12-13 - encodes the beta subunit of the high-affinity IgE receptor (FcεRI)
Chromosome 5 - encodes Th2-promoting cytokines (IL-4, IL-13), the TIM gene family (regulates Th1/Th2 balance), the p40 subunit of IL-12, and the β2 adrenergic receptor

Polymorphisms in the IL-4 gene receptor (chromosome 16p12) and the FcεRI β subunit are also implicated.

Environmental Factors

Allergen exposure (dose and duration)
Air pollution (diesel exhaust, SO₂, ozone)
Hygiene hypothesis: reduced exposure to infections in early childhood (due to improved sanitation, antibiotics, smaller family size) may shift the immune balance toward Th2 responses, predisposing to allergy
Route of sensitization: respiratory sensitization is more likely to produce airway disease

Basic Mechanisms - The Four Types of Hypersensitivity

Allergic and autoimmune disorders share similar mechanisms of tissue damage. These are organized into four types of hypersensitivity (Coombs and Gell Classification):

Mechanisms of hypersensitivity - immune activation, effectors, and tissue events across Types I-IV

Figure 13.7 - Mechanisms of hypersensitivity (APC = antigen presenting cell; MC = mast cell; Th1 = T helper 1 cell)

Type	Name	Mechanism	Effector	Tissue Effect
I	Immediate / Reaginic	Allergen cross-links IgE on mast cells	IgE + Mast cell	Vasodilatation, increased permeability, smooth muscle contraction
II	Cytotoxic	Antibody (IgG/IgA/IgM) binds cell surface or basement membrane	Complement + Neutrophils	Membrane damage, cell lysis
III	Immune complex	Ag-Ab complexes deposit in tissues	Complement + Neutrophils	Tissue damage
IV	Cell-mediated (Delayed)	T cells + macrophages; no antibody	Cytokines (IL-2, IFN-γ) activating Tc cells + macrophages	Tissue damage

In allergic rhinitis and asthma, all four types can be involved at different phases. Chronic allergic inflammation is essentially a Type IV pattern in nature.

Phase Responses in Allergy

Immediate Phase (0-60 minutes)

Allergen cross-links IgE already bound to FcεRI on mast cells and basophils
Degranulation releases preformed mediators (histamine, tryptase, heparin)
Rapid synthesis of lipid mediators (prostaglandins, leukotrienes, PAF)
Clinical result: sneezing, itch, rhinorrhoea within minutes

Late Phase Response (2-24 hours)

Involves Th2 cytokines (IL-4, IL-5, IL-13)
Activation and recruitment of eosinophils and other leucocytes
Nasal blockage predominates

Chronic Allergic Inflammation

Characterized by tissue destruction and remodelling
Driven by persistent eosinophilic infiltration and Th2 skewing
This phase is essentially Type IV (cell-mediated) hypersensitivity in nature

Effector Cells of Allergic Disease

Mast Cells

Mast cells are haemopoietic stem cell derivatives that mature locally in tissues. They reside near body surfaces exposed to allergens (mucosal mast cells and tissue mast cells), often close to blood vessels.

Express FcεRI (high-affinity IgE receptor) - tightly binds sIgE even at very low serum concentrations
Also express FcεRII (CD23) - low affinity IgE receptor; exact role in allergy not fully understood
Granules contain preformed mediators responsible for immediate symptoms

On allergen exposure → allergen cross-links FcεRI-bound IgE → intracellular signalling → degranulation

Basophils

Develop from bone marrow granulocyte-monocyte progenitors (unlike mast cells)
Respond to multiple stimuli: cytokines, antibodies, proteases, antigens
Cross-linking of IgE-bound FcεRI on basophils produces mediators similar to mast cells
Found in nasal washes of allergic rhinitis patients - their role is increasingly recognized

Eosinophils

Recruited by IL-5 and eotaxin
Express FcεRI at low levels
Release major basic protein (MBP), eosinophil peroxidase, eosinophil-derived neurotoxin
Responsible for late-phase mucosal damage and remodelling

Dendritic Cells (DCs)

Professional antigen presenting cells that capture allergen in the mucosa
Migrate to draining lymph nodes to present allergen peptides to naive T cells
Myeloid DCs induce Th2 differentiation (pro-allergic)
Plasmacytoid DCs (CD123+) increase dramatically after repeated allergen challenge and can also induce Th2 development in vitro
DC recruitment to bronchial mucosa occurs within the time frame of late asthmatic responses

IgE: Central Mediator of Allergy

Th2 development and IgE production - from APC-T cell interaction through to IgE-coated mast cell

Figure 14.2 - Th2 development and IgE production

IgE is the lowest concentration immunoglobulin in human serum (approximately 100-400 ng/mL). Most IgE is tissue-bound (half-life ~2 days in circulation but months when bound to FcεRI on mast cells).

How IgE Is Produced:

Allergen is taken up by a dendritic cell (APC) and presented via MHC II to a naive Th0 cell via TCR, with co-stimulation through B7-CD28
In the presence of IL-4 (from the local environment), Th0 differentiates into Th2 cells
Th2 cells secrete IL-4 and IL-13, which drive B cell isotype switching from IgM → IgE
Plasma cells secrete IgE
IgE binds to FcεRI on mast cells - the cell is now sensitized and ready to react on next allergen exposure

IgE production occurs mainly in bone marrow and draining regional lymph nodes, but local IgE production has been reported in some forms of allergic rhinitis (see Local Allergic Rhinitis below).

Key cytokines in IgE production:

IL-4 and IL-13 (from Th2 cells) - promote IgE class switching
IL-4 and IL-13 are also released from mast cells during degranulation, creating a positive feedback loop perpetuating IgE production

High-Affinity Receptor (FcεRI) Signalling in Allergic Reaction

This is the core molecular event in Type I hypersensitivity:

Sensitization phase: IgE (specific to an allergen) binds to FcεRI on the mast cell surface - the cell is now "primed"
Re-exposure: The same allergen enters the tissue and cross-links two or more adjacent FcεRI-IgE complexes
Cross-linking triggers intracellular signalling:
- Activation of tyrosine kinases (Lyn, Syk)
- Phospholipase C activation → IP3 and DAG → calcium mobilization
- Activation of protein kinase C
This results in:
- Degranulation - release of preformed granule mediators (histamine, tryptase, chymase, heparin, carboxypeptidase A)
- Rapid synthesis of lipid mediators (prostaglandins via COX pathway; leukotrienes via lipoxygenase pathway; PAF)
- Later transcription and production of cytokines (TNF-α, IL-4, IL-13, IL-5) for late phase responses

Key Mediators and Their Actions

Mediator	Source	Action
Histamine	Mast cell/basophil granules	Vasodilatation, increased vascular permeability, smooth muscle contraction, pruritus
Tryptase	Mast cell granules	Tissue destruction; marker of mast cell activation (elevated in 60% of anaphylaxis)
Chymase	Mast cell granules	Connective tissue remodelling
Leukotrienes (LTC4, LTD4)	Rapidly synthesized	Potent bronchoconstriction, increased mucus secretion
Prostaglandins (PGD2)	Rapidly synthesized	Vasodilation, mucus secretion
PAF (Platelet Activating Factor)	Mast cells, eosinophils	Elevated in 100% of anaphylaxis; platelet activation, bronchoconstriction
IL-4, IL-13	Mast cells, Th2 cells	Amplify Th2 response, promote IgE production
IL-5	Th2 cells	Eosinophil activation and survival
TNF-α	Mast cells	Promotes inflammation
Eosinophil Major Basic Protein (MBP)	Eosinophils	Toxic to parasites and epithelium; triggers histamine release from mast cells

Histamine note: Highly soluble and rapidly diffuses - metabolized within minutes by histamine N-methyl transferase, monoamine oxidase, and diamine oxidase. Its short half-life limits its use as a laboratory marker (unlike tryptase).

Role of Sensory Nerves in Allergic Rhinitis

Neurogenic mechanisms amplify allergic inflammation:

Mast cell mediators directly activate sensory nerve endings in nasal mucosa
Activated sensory nerves release neuropeptides - Substance P and neurokinin
These neuropeptides further promote vasodilation, glandular secretion, and inflammatory cell recruitment (neurogenic inflammation)
Neurogenic inflammation is self-perpetuating - an important component of the allergen-IgE interaction
Nerve growth factor (NGF) is detectable in nasal fluid in chronic allergic rhinitis and increases after allergen challenge
Hyper-responsiveness of target organs (nasal mucosa) relates to a combination of chronic inflammation AND increased sensory nerve activation

Local Allergic Rhinitis (LAR)

A clinically important concept: Local Allergic Rhinitis (LAR) describes a localized nasal allergic response occurring in patients who:

Have negative systemic skin prick tests
Have normal serum sIgE
Yet mount a genuine IgE-mediated local mucosal allergic response to allergens

This is explained by local IgE synthesis within the nasal mucosa itself, rather than systemic sensitization. LAR may explain why some sensitized individuals develop rhinitis while others develop asthma or eczema, and why others have sensitization with no clinical manifestation.

Clinical Features of IgE-Mediated Hypersensitivity

Lifetime prevalence of anaphylaxis is estimated at 0.05-2.0%. The clinical manifestations reflect mediator effects across multiple systems:

System	Manifestations
Prodromal	Anxiety, paraesthetic sensations on palms and soles
Cutaneous	Pruritus, flushing, urticaria, angioedema
Respiratory	Rhinorrhoea, sneezing, bronchospasm, laryngeal oedema
Cardiovascular	Hypotension, tachycardia, arrhythmias (T-wave inversion, SVT, bundle branch block), myocardial infarction
Gastrointestinal	Nausea, vomiting, abdominal cramps, diarrhoea

IV allergen (e.g. drug) → anaphylaxis within seconds
General immediate allergy → within 60 minutes of allergen exposure
Biphasic reactions → immediate + late phase reactions occurring together

Post-mortem in fatal anaphylaxis typically shows: airway oedema, laryngeal oedema, pulmonary hyperinflation, pulmonary oedema, eosinophilic infiltration around bronchi, and swelling of liver/spleen/intestine.

Key Points Summary

Concept	Key Fact
Allergy definition	Hypersensitivity reaction via specific immunologic mechanisms
Atopy prevalence	Up to 40% in industrialized countries
Main IgE receptor	FcεRI (high affinity) on mast cells, basophils, eosinophils
IgE concentration	Lowest of all immunoglobulin isotypes (100-400 ng/mL)
Key cytokines for IgE switching	IL-4 and IL-13 (from Th2 cells)
Immediate mediator	Histamine - metabolized within minutes
Best anaphylaxis marker	PAF elevated in 100%; tryptase in 60%; histamine in 70%
Neurogenic amplification	Substance P and neurokinin from sensory nerves
Local Allergic Rhinitis	Local IgE production without systemic sensitization

Scott-Brown's Otorhinolaryngology Head & Neck Surgery, Vol. 1, Chapter 14 - pp. 137-148

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