What is the mechanism of allergic rhinitis?

Mechanism of Allergic Rhinitis

Allergic rhinitis is fundamentally an IgE-mediated inflammatory disease triggered when allergens penetrate the nasal epithelial barrier, initiating a Th2-dominant immune response that produces allergen-specific IgE antibodies and recruits inflammatory cells—particularly mast cells, basophils, and eosinophils—resulting in both immediate and late-phase allergic reactions. 1, 2

Initial Sensitization Phase

The pathogenesis begins with allergen sensitization, a critical first step that occurs before symptoms ever develop:

• Dendritic cells expressing CD1a and CD11c in the nasal epithelium process inhaled allergens and present allergenic peptides via MHC II molecules to T-cell receptors on resting CD4+ cells in regional lymph nodes 1
• With appropriate costimulatory signals, these allergen-stimulated T cells proliferate into Th2-biased cells that produce IL-3, IL-4, IL-13, IL-5, and GM-CSF 1
• This Th2 cytokine profile promotes B-cell isotype switching to produce allergen-specific IgE antibodies by plasma cells, while simultaneously promoting mast cell proliferation and eosinophilic infiltration into the nasal mucosa 1
• The imbalance between Th2 and Th1 cells, favoring Th2, plays a critical role in regulating IgE synthesis and cell recruitment at sites of allergic inflammation 1

A critical caveat: synthesis of allergen-specific IgE is required for allergic rhinitis development, but many individuals with allergen-specific IgE never develop symptoms, indicating that IgE presence alone is insufficient for disease expression 1

Early-Phase Allergic Response

Upon re-exposure to allergens in sensitized individuals, the immediate reaction occurs within minutes:

• Cross-linking of IgE antibodies bound to mast cell surfaces by allergen triggers immediate degranulation and release of preformed mediators, primarily histamine, along with tryptase, leukotrienes, and prostaglandins 1, 3, 4
• Histamine acts predominantly through H1-receptors to induce the characteristic neurally-mediated symptoms: nasal itching, paroxysms of sneezing, and watery rhinorrhea 4
• Histamine also causes vascular effects leading to nasal congestion, though this is less prominent in the early phase 4
• Basophils also contribute to histamine generation during this phase 1, 4

Important clinical point: histamine nasal insufflation reproduces all symptoms of allergic rhinitis, and H1-receptor antagonists reduce symptoms by approximately 40-50%, with greatest effect on neurally-mediated responses—demonstrating that histamine is a major but not sole mediator 4

Late-Phase Allergic Response

The late-phase response develops 4 to 8 hours after allergen exposure and involves sustained inflammation:

• Mast cell-derived cytokines (IL-4, IL-5, IL-6, IL-8, GM-CSF, and RANTES) orchestrate cellular infiltration by upregulating adhesion molecules such as VCAM-1 and E-selectin on endothelial cells 1, 3
• These adhesion molecules cause circulating eosinophils, basophils, and T-lymphocytes to adhere to endothelial cells before migrating through the endothelium into nasal tissue (diapedesis) 3
• Tissue infiltration is characterized by CD4+ T-cells, CD25+ T-cells in the submucosa and epithelium, along with activated eosinophils and basophils 1
• Infiltrating cells release additional mediators including leukotrienes, kinins, and cytokines that perpetuate inflammation 3
• Leukotrienes are particularly potent mediators of nasal vascular congestion and plasma protein exudation, contributing to anterior nasal secretions 4

The late-phase response is dominated by nasal congestion rather than the sneezing and itching of the early phase 1

Cellular and Molecular Characteristics

The inflammatory infiltrate has distinct features:

• Eosinophils accumulate in both the lamina propria and epithelium in an activated state, with numbers correlating with pulmonary function abnormalities and bronchial hyperresponsiveness 1, 4
• Increased numbers of mast cells, T cells, and Langerhans cells (which induce T-cell activation) are found within the epithelium 4
• Epithelial cells themselves generate chemokines and cytokines that orchestrate cellular recruitment, making them active participants rather than passive barriers 4
• Recruited eosinophils contribute to their own persistence through autocrine mechanisms 4

Priming Effect

Repeated allergen challenges increase sensitivity over time through a priming effect: the amount of allergen required to induce an immediate response decreases with ongoing exposure due to inflammatory cell influx during repeated late-phase responses 1

This priming phenomenon provides the rationale for initiating anti-inflammatory therapies before the pollen season or before chronic allergen exposures, rather than waiting for symptoms to develop 1

Genetic and Environmental Factors

• Atopy (the predisposition to develop IgE to common inhaled allergens) has strong familial tendency, typically starting in childhood or adolescence 1
• Genome-wide searches have identified associations with markers on more than 14 chromosome pairs, though the complex inheritance mechanisms remain incompletely understood 1
• Environmental factors interact critically with genetic predisposition at the gene-environment interface to determine disease expression 1

Neural Mechanisms

Neuronal reflexes mediate local responses to inflammatory mediators and may participate in T-lymphocyte activation, contributing to symptom generation beyond direct mediator effects 3