Nasal allergen-neutralizing IgG4 antibodies block IgE-mediated responses: Novel biomarker of subcutaneous grass pollen immunotherapy

Abstract

Background: Grass pollen subcutaneous immunotherapy (SCIT) is associated with induction of serum IgG₄-associated inhibitory antibodies that prevent IgE-facilitated allergen binding to B cells.

Objective: We sought to determine whether SCIT induces nasal allergen-specific IgG₄ antibodies with inhibitory activity that correlates closely with clinical response.

Methods: In a cross-sectional controlled study, nasal fluid and sera were collected during the grass pollen season from 10 SCIT-treated patients, 13 untreated allergic patients (with seasonal allergic rhinitis [SAR]), and 12 nonatopic control subjects. Nasal and serum IgE and IgG₄ levels to Phleum pratense components were measured by using the Immuno Solid Allergen Chip microarray. Inhibitory activity was measured by IgE-facilitated allergen binding assay. IL-10⁺ regulatory B cells were quantified in peripheral blood by using flow cytometry.

Results: Nasal and serum Phl p 1- and Phl p 5-specific IgE levels were increased in patients with SAR compared to nonatopic control subjects (all, P < .001) and SCIT-treated patients (nasal, P < .001; serum Phl p 5, P = .073). Nasal IgG₄ levels were increased in the SCIT group compared to those in the SAR group (P < .001) during the pollen season compared to out of season. IgG-associated inhibitory activity in nasal fluid and serum was significantly increased in the SCIT group compared to that in the SAR (both, P < .01). The magnitude of the inhibitory activity was 93% (P < .001) in nasal fluid compared to 66% (P < .001) in serum and was reversed after depletion of IgG. Both nasal fluid (r = -0.69, P = .0005) and serum (r = -0.552, P = .0095) blocking activity correlated with global symptom improvement. IL-10⁺ regulatory B cells were increased in season compared to out of season in the SCIT group (P < .01).

Conclusion: For the first time, we show that nasal IgG₄-associated inhibitory activity correlates closely with the clinical response to allergen immunotherapy in patients with allergic rhinitis with or without asthma.

Keywords: Biomarkers of allergen immunotherapy; IgA(1); IgA(2); IgE-facilitated allergen binding; IgG(4); allergic rhinoconjunctivitis with and without asthma; blocking antibodies; subcutaneous immunotherapy.