Mechanisms of Allergen Immunotherapy in Allergic Rhinitis

Abstract

Purpose of review: Allergic rhinitis (AR) is a chronic inflammatory immunoglobulin (Ig) E-mediated disease of the nasal mucosa that can be triggered by the inhalation of seasonal or perennial allergens. Typical symptoms include sneezing, rhinorrhea, nasal itching, nasal congestion and symptoms of allergic conjunctivitis. AR affects a quarter of the population in the United States of America and Europe.

Recent findings: AR has been shown to reduce work productivity in 36-59% of the patients with 20% reporting deteriorated job attendance. Moreover, 42% of children with AR report reduced at-school productivity and lower grades. Most importantly, AR impacts the patient's quality of life, due to sleep deprivation. However, a proportion of patients fails to respond to conventional medication and opts for the allergen immunotherapy (AIT), which currently is the only disease-modifying therapeutic option. AIT can be administered by either subcutaneous (SCIT) or sublingual (SLIT) route. Both routes of administration are safe, effective, and can lead to tolerance lasting years after treatment cessation. Both innate and adaptive immune responses that contribute to allergic inflammation are suppressed by AIT. Innate responses are ameliorated by reducing local mast cell, basophil, eosinophil, and circulating group 2 innate lymphoid cell frequencies which is accompanied by decreased basophil sensitivity. Induction of allergen-specific blocking antibodies, immunosuppressive cytokines, and regulatory T and B cell phenotypes are key pro-tolerogenic adaptive immune responses.

Conclusion: A comprehensive understanding of these mechanisms is necessary for optimal selection of AIT-responsive patients and monitoring treatment efficacy. Moreover, it could inspire novel and more efficient AIT approaches.

Keywords: Allergen immunotherapy; Allergic rhinitis; B cell; Dendritic cells; Innate and adaptive immune response; Innate lymphoid cells; T cells.

Fig. 1

The biphasic response of allergic rhinitis following nasal allergen challenge (NAC). In the early phase, tryptase and total nasal symptom scores (TNSS) peak at 5 min post challenge which is accompanied by deterioration of peak nasal inspiratory flow (PNIF). Eosinophilic cationic protein (ECP), eotaxin, and T_H2-related cytokines gradually increase and peak at 8 h during the late phase response which is paralleled by ongoing nasal congestion. Created with BioRender.com

Fig. 2

Mechanisms of allergic sensitization and allergen immunotherapy (AIT). (A) Upon inhalation of the allergen, ECs recruit DCs and polarize them to a pro-allergic DC2 phenotype. These cells uptake the allergen and migrate to lymph nodes, where they present it to naïve T cells and promote the development of T_H2 and T_FH subsets. T_FH and T_H2 cells collectively facilitate B cell maturation and class-switch recombination which leads to allergen-specific IgE production. These IgE molecules bind to high-affinity receptors on basophil and mast cell surfaces this way sensitizing the patient. The early phase reactions are triggered when a sensitized individual is subsequently exposed to the allergen, which in turn cross-links neighboring IgE molecules on basophil and mast cell surfaces and prompts the release of vasodilatory and chemoattractive mediators. This facilitates the recruitment of late phase effector T cells and eosinophils. (B) AIT suppresses the development of DC2 phenotype and promotes naïve T cell differentiation to regulatory phenotypes (iTregs, FOXP3⁺Tregs, T_FR cells). These subsets in turn suppress T_H2, T_H2A and T_FH responses and favor the differentiation of T_H1. Inhibition of T_H2 responses results in reduced local eosinophilia and prevents the development of IgE⁺ plasma cells. AIT also induces Bregs and IgG⁺/IgA⁺ plasma cells which produce blocking antibodies that compete with IgE for binding to the allergen, preventing the cross-linking of high-affinity receptors on mast cell and basophil surfaces and inhibiting their degranulation. Red arrows represent inhibition of effector cells; green arrows represent AIT-induced regulatory phenotypes and their effects; black arrows represent increases or decreases of the population frequencies. EC, epithelial cells; DC, dendritic cells; T_H2, T helper type 2 cell; T_FH, T follicular helper cell; Treg, T regulatory cell; Breg, B regulatory cell. Created with BioRender.com