Local Respiratory Allergy: From Rhinitis Phenotype to Disease Spectrum

Abstract

Local respiratory allergy (LRA) is defined by the negativity of atopy tests, a clinical history suggestive of airway allergy and a positive response to the nasal and/or bronchial allergen challenge. The clinical spectrum of LRA is comprised of three conditions: local allergic rhinitis (LAR) and local allergic asthma in non-atopic patients, and dual allergic rhinitis (coexistence of allergic rhinitis and LAR) in atopic individuals. LRA is an independent disease phenotype not progressing to atopy over time, but naturally evolving to the clinical worsening and the onset of comorbidities. Published data suggests that LRA is mediated through the mucosal synthesis of allergen-specific (s)IgE, which binds to FcϵRI on resident mast cells, and in >50% of cases traffics to the blood stream to sensitize circulating basophils. To date, 4 clinical trials have demonstrated the capacity of allergen immunotherapy (AIT) to decrease nasal, conjunctival and bronchial symptoms, to improve quality of life, to increase the threshold dose of allergen eliciting respiratory symptoms, and to induce serum sIgG₄ in LRA individuals. Collectively, these data indicate that local allergy is a relevant disease mechanisms in both atopic and non-atopic patients with airway diseases.

Keywords: IgE synthesis; allergic rhinitis; dual allergic rhinitis; local allergic asthma; local allergic rhinitis; local respiratory allergy; mucosal immunology.

Figure 1

Synthesis of allergen-specific (s)IgE in the airway mucosa of atopic respiratory allergy (ARA) and local respiratory allergy (LRA) patients. CD1c+ myeloid dendritic cells take up the allergen and travel to the secondary lymphoid tissues. Here, dendritic cells activate allergen-specific naïve CD4+ T lymphocytes to give rise to Th1 and Th2 cells. Th1 cells communicate with allergen-specific IgM+ naïve B cells and promote their class switch recombination (CSR) to IgG, and their somatic hypermutation, which ultimately generates IgG+ memory B cells. The immunoglobulins produced by IgG+ memory B cells show a high affinity for the allergen. Allergen-specific Th1 and IgG+ B cells exit the lymphoid tissue and gain access to the blood stream. Th2 cells in the germinal centers also communicate with IgM+ naïve B cells to promote their CSR to IgE. Nevertheless, IgE+ B cells cannot undergo somatic hypermutation in an efficient manner, and they die by apoptosis before exiting the lymphoid tissue. On the other hand, allergen-specific Th2 cells reach the blood stream and gain access to the airway mucosa, together with Th1 cells (not shown) and IgG+ memory B cells. Upon allergen re-exposure (not shown), IgG+ memory B cells undergo sequential CSR to IgE if they are stimulated by IL-4 provided by Th2 cells or basophils. This process generates IgE+ plasma cells releasing high amounts of high-affinity sIgE. Mucosal sIgE binds to FcϵRI expressed on resident mast cells and sensitize them for activation. After saturating FcϵRI receptors in the mucosa, sIgE traffics through the lymphoid vessels to the blood stream to bind to FcϵRI on circulating basophils. In ARA subjects, there is enough sIgE to saturate the receptor system of blood basophils and sIgE binds subsequently to FcϵRI on the surface of mast cells at peripheral tissues, like the skin. After saturating the FcϵRI receptor system of the whole organism, sIgE is found free in serum and in the airway secretions of ARA individuals. In patients with LRA, the sIgE synthetized at the mucosal level is sufficient to saturate FcϵRI on mucosal resident mast cells, and in >50% of cases is also enough to sensitize peripheral basophils. Nevertheless, LRA patients do not have sufficient sIgE to saturate FcϵRI on peripheral basophils, and thus sIgE is not found on skin mast cells or serum. Most patients with LRA do not have sIgE in respiratory secretions either, although low levels are sometimes detected. This phenomenon probably corresponds to a small sIgE leakage through the epithelium, before the antibody exits the mucosa via the lymphatic system.

Figure 2

Diagnostic algorithm of chronic rhinitis phenotypes. BAT, basophil activation test; NAC, nasal allergen challenge; sIgE, allergen-specific IgE; SPT, skin prick test. *The interrogation about the seasonality and severity variations of nasal symptoms, and about the specific (vegetation, furry animals, dust, etc.) and unspecific triggers of rhinitis (rapid changes in temperature or humidity, irritant smells, etc.) are useful means to investigate the likelihood of an allergic etiology for the disease or to evaluate whether positive skin prick test results are consistent with the symptoms pattern.